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Nakajima M, Yamazaki H, Yoshinari K, Kobayashi K, Ishii Y, Nakai D, Kamimura H, Kume T, Saito Y, Maeda K, Kusuhara H, Tamai I. Contribution of Japanese scientists to drug metabolism and disposition. Drug Metab Dispos 2025; 53:100071. [PMID: 40245580 DOI: 10.1016/j.dmd.2025.100071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/18/2025] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
Japanese researchers have played a pivotal role in advancing the field of drug metabolism and disposition, as demonstrated by their substantial contributions to the journal Drug Metabolism and Disposition (DMD) over the past 5 decades. This review highlights the historical and ongoing impact of Japanese scientists on DMD, celebrating their achievements in elucidating drug metabolism, membrane transport, pharmacokinetics, and toxicology. From the discovery of cytochrome P450 by Tsuneo Omura and Ryo Sato in 1962 to subsequent advances in drug transport research, Japan has maintained a leading position in the field. A geographical analysis of DMD publications reveals a notable increase in contributions from Japan during the 1980s, ranking second globally and maintaining this position through the 2000s. However, recent years have seen a slight decline in output, likely influenced by the COVID-19 pandemic and increased online journals as well as structural changes within academia and industry. Importantly, this trend is not unique to Japan. To sustain excellence and innovation in this field, it is crucial to strengthen funding for absorption, distribution, metabolism, excretion, and toxicity research and promote collaborations between academia, industry, and regulatory agencies. By prioritizing the translation of fundamental discoveries into drug development and clinical applications, scientists in this area can further advance global efforts toward achieving optimal drug efficacy and safety. This review underscores the enduring contributions of Japanese researchers to DMD and calls for renewed efforts to drive innovation and progress in this vital area of science. SIGNIFICANCE STATEMENT: Over the past 5 decades, Japanese scientists have made significant contributions to Drug Metabolism and Disposition through groundbreaking discoveries and advancements in the study of drug-metabolizing enzymes, transporters, pharmacokinetics analysis, and related areas. These contributions continue to shape the field, offering a foundation for future innovation in this area. We hope that the next generation of Japanese scientists will further solidify their global leadership in this area to advance drug development and proper pharmacotherapy.
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Affiliation(s)
- Miki Nakajima
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan; WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
| | - Hiroshi Yamazaki
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan
| | - Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kaoru Kobayashi
- Department of Biopharmaceutics, Graduate School of Clinical Pharmacy, Meiji Pharmaceutical University, Tokyo, Japan
| | - Yuji Ishii
- Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Daisuke Nakai
- Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, Tokyo, Japan
| | | | | | - Yoshiro Saito
- National Institute of Health Sciences, Kanagawa, Japan
| | - Kazuya Maeda
- School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ikumi Tamai
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
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Fukase T, Doi S, Dohi T, Koike T, Nishio R, Yasuda H, Takeuchi M, Takahashi N, Chikata Y, Endo H, Nishiyama H, Okai I, Iwata H, Okazaki S, Daida H, Suwa S, Minamino T, Miyauchi K. Impact of Low-Dose Prasugrel on Platelet Reactivity in Chronic Phase of Post-Percutaneous Coronary Intervention (CHAPERON): a Prospective Cohort Study. Cardiovasc Drugs Ther 2024; 38:947-957. [PMID: 37097381 DOI: 10.1007/s10557-023-07454-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/18/2023] [Indexed: 04/26/2023]
Abstract
PURPOSE Asians often face the problems of clopidogrel resistance and East Asian paradox. This study aimed to evaluate the effects of P2Y12 inhibitors, including low-dose prasugrel 2.5 mg, on the P2Y12 reaction unit (PRU) in the chronic phase after percutaneous coronary intervention (PCI). METHODS A total of 348 patients were studied. PRU was measured 6-12 months after PCI and subsequently, 6 months later using a P2Y12 assay, respectively. This study evaluated the proportion of bleeding risk (PRU ≤ 85) and ischemic risk (PRU ≥ 239) as primary endpoints, and the prediction of bleeding risk and ischemic risk using multivariable logistic regression analysis. RESULTS At baseline, 136 patients (39%) received prasugrel 3.75 mg, 48 patients (14%) received prasugrel 2.5 mg, and 164 patients (47%) received clopidogrel 75 mg. Clopidogrel 75 mg had a significantly higher proportion of ischemic risk within one year after PCI than the other groups, and was an independent predictor for ischemic risk with reference of prasugrel 3.75 mg. In addition, switching from clopidogrel 75 mg to prasugrel 2.5 mg significantly lowered and aggregated the PRU value. Whereas, dose reduction of prasugrel had a significantly lower proportion of bleeding risk over one year after PCI than the continuation of prasugrel 3.75 mg, and was an independent predictor for bleeding risk with reference of continuation of prasugrel 3.75 mg. CONCLUSIONS Prasugrel 2.5 mg has a lower ischemic risk and a more stable PRU value compared with clopidogrel treatment. Prasugrel also contributes to a decline in bleeding risk with concomitant dose reduction. TRIAL REGISTRATION University Hospital Medical Information Network (UMIN), ID: UMIN000029541, Date: October 16, 2017 ( https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033395 ).
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Affiliation(s)
- Tatsuya Fukase
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Shinichiro Doi
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Tomotaka Dohi
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Takuma Koike
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Ryota Nishio
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Hidetoshi Yasuda
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Mitsuhiro Takeuchi
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Norihito Takahashi
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Yuichi Chikata
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Hirohisa Endo
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Hiroki Nishiyama
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Iwao Okai
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Hiroshi Iwata
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Shinya Okazaki
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Hiroyuki Daida
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
- Department of Radiological Technology, Faculty of Health Science, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Satoru Suwa
- Department of Cardiology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni-Shi, 410-2295, Sizuoka, Japan
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
- Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-Ku, Tokyo, 100-0004, Japan
| | - Katsumi Miyauchi
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
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Tan BH, Ahemad N, Pan Y, Ong CE. Mechanism-based inactivation of cytochromes P450: implications in drug interactions and pharmacotherapy. Xenobiotica 2024; 54:575-598. [PMID: 39175333 DOI: 10.1080/00498254.2024.2395557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/17/2024] [Accepted: 08/19/2024] [Indexed: 08/24/2024]
Abstract
Cytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20-30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics.
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Affiliation(s)
- Boon Hooi Tan
- Division of Applied Biomedical Sciences and Biotechnology, International Medical University, Kuala Lumpur, Malaysia
| | - Nafees Ahemad
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Selangor, Malaysia
| | - Yan Pan
- Department of Biomedical Science, University of Nottingham Malaysia Campus, Semenyih, Selangor, Malaysia
| | - Chin Eng Ong
- School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
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Lin Z, Yuan S, He J, Song Y, Zhang W, Dou K. Novel insights on dual antiplatelet therapy duration following stenting for angiography-detected moderate-to-severe calcified coronary lesions. Pharmacol Res 2024; 208:107378. [PMID: 39216842 DOI: 10.1016/j.phrs.2024.107378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/24/2024] [Accepted: 08/24/2024] [Indexed: 09/04/2024]
Abstract
Dual antiplatelet therapy (DAPT), comprising both aspirin and the P2Y12 receptor inhibitor, is crucial in managing patients with coronary artery disease following percutaneous coronary intervention (PCI). The optimal duration for DAPT in patients with angiography-detected moderate-to-severe calcified coronary (MSCC) lesions who underwent PCI with drug-eluting stents (DES) implantation remains uncertain. We recruited patients with angiography-detected MSCC lesions who received DES implantation from the prospective Fuwai Percutaneous Coronary Intervention Registry. Patients were classified into two groups according to the duration of DAPT: those with a DAPT duration of one year or less, and those with a DAPT duration of more than one year. The primary endpoint was the major adverse cardiovascular and cerebrovascular event, which was defined as composed of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. The key-safety endpoint was bleeding type 2, 3, or 5 according to the Bleeding Academic Research Consortium criteria. There were 1730 patients included in the study, and 470 (27.17%) continued DAPT for more than one year after undergoing MSCC-PCI with DES implantation. The median follow-up time was 2.5 years. DAPT>1-year versus ≤1-year DAPT was significantly associated with a reduced risk of the primary outcome (1.59% versus 3.19%; adjusted hazard ratio=0.44; 95% CI: 0.22-0.88). Similar trends were observed for all-cause death (0.16% versus 1.91%; P<0.001) and cardiovascular death (0.08% versus 1.06%; P=0.001). There was no significant difference in the key-safety endpoint between 2 regimens (1.75% versus 0.85%; adjusted hazard ratio=1.95; 95% CI: 0.65-5.84). In conclusion, long-term DAPT after DES implantation in patients with MSCC lesions resulted in improved clinical outcomes at 2.5 years. This was achieved by reducing the risk of ischemia without increasing clinically significant bleeding.
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Affiliation(s)
- Zhangyu Lin
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cardiometabolic Medicine Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Cardiovascular Disease, Beijing, China
| | - Sheng Yuan
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cardiometabolic Medicine Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Cardiovascular Disease, Beijing, China
| | - Jining He
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cardiometabolic Medicine Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Cardiovascular Disease, Beijing, China
| | - Yanjun Song
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cardiometabolic Medicine Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Cardiovascular Disease, Beijing, China
| | - Wenjia Zhang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Kefei Dou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cardiometabolic Medicine Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Cardiovascular Disease, Beijing, China; National Clinical Research Center for Cardiovascular Diseases, Beijing, China.
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5
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Zhu T, Wu Y, Li XM, Jia YM, Zhou H, Jiang LP, Tai T, Mi QY, Ji JZ, Xie HG. Vicagrel is hydrolyzed by Raf kinase inhibitor protein in human intestine. Biopharm Drug Dispos 2022; 43:247-254. [PMID: 36519186 DOI: 10.1002/bdd.2340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 11/12/2022] [Accepted: 11/17/2022] [Indexed: 12/23/2022]
Abstract
As an analog of clopidogrel and prasugrel, vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2-oxo-clopidogrel (also the precursor of active thiol metabolite H4) in human intestine, predominantly by AADAC and CES2; however, other unknown vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2-oxo-clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC50 value of inhibition of rhRKIP-catalyzed vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed vicagrel in vitro, with the values of Km , Vmax , and CLint measured as 20.04 ± 1.99 μM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC50 value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of vicagrel in the human intestine, and that vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.
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Affiliation(s)
- Ting Zhu
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Department of Clinical Pharmacy, College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yu Wu
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xue-Mei Li
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yu-Meng Jia
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Department of Clinical Pharmacy, College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Huan Zhou
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Department of Clinical Pharmacy, College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Li-Ping Jiang
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Department of Clinical Pharmacy, College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ting Tai
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Department of Clinical Pharmacy, College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qiong-Yu Mi
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jin-Zi Ji
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hong-Guang Xie
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Department of Clinical Pharmacy, College of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.,Department of Clinical Pharmacy, Nanjing Medical University School of Pharmacy, Nanjing, China
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6
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Kuszynski DS, Lauver DA. Pleiotropic effects of clopidogrel. Purinergic Signal 2022; 18:253-265. [PMID: 35678974 DOI: 10.1007/s11302-022-09876-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 05/26/2022] [Indexed: 01/04/2023] Open
Abstract
Clopidogrel is a widely prescribed prodrug with anti-thrombotic activity through irreversible inhibition of the P2Y12 receptor on platelets. It is FDA-approved for the clinical management of thrombotic diseases like unstable angina, myocardial infarction, stroke, and during percutaneous coronary interventions. Hepatic clopidogrel metabolism generates several distinct metabolites. Only one of these metabolites is responsible for inhibiting the platelet P2Y12 receptor. Importantly, various non-hemostatic effects of clopidogrel therapy have been described. These non-hemostatic effects are perhaps unsurprising, as P2Y12 receptor expression has been reported in multiple tissues, including osteoblasts, leukocytes, as well as vascular endothelium and smooth muscle. While the "inactive" metabolites have been commonly thought to be biologically inert, recent findings have uncovered P2Y12 receptor-independent effects of clopidogrel treatment that may be mediated by understudied metabolites. In this review, we summarize both the P2Y12 receptor-mediated and non-P2Y12 receptor-mediated effects of clopidogrel and its metabolites in various tissues.
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Affiliation(s)
- Dawn S Kuszynski
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, Michigan State University, 1355 Bogue Street, B336 Life Science, East Lansing, MI, USA.,Institute of Integrative Toxicology, Michigan State University, East Lansing, MI, USA
| | - D Adam Lauver
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, Michigan State University, 1355 Bogue Street, B336 Life Science, East Lansing, MI, USA.
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Deiab GIA, Saadah LM, Basheti IA. Using drug chemical structures in the education of pharmacology and clinical therapeutics key concepts. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e21070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
| | | | - Iman Amin Basheti
- Applied Science Private University, Jordan; The University of Sydney, Australia
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8
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Schilling U, Dingemanse J, Ufer M. Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists. Clin Pharmacokinet 2021; 59:545-566. [PMID: 32056160 DOI: 10.1007/s40262-020-00864-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Coronary artery disease remains the major cause of mortality worldwide. Antiplatelet drugs such as acetylsalicylic acid and P2Y12 receptor antagonists are cornerstone treatments for the prevention of thrombotic events in patients with coronary artery disease. Clopidogrel has long been the gold standard but has major pharmacological limitations such as a slow onset and long duration of effect, as well as weak platelet inhibition with high inter-individual pharmacokinetic and pharmacodynamic variability. There has been a strong need to develop potent P2Y12 receptor antagonists with more favorable pharmacological properties. Prasugrel and ticagrelor are more potent and have a faster onset of action; however, they have shown an increased bleeding risk compared with clopidogrel. Cangrelor is highly potent and has a very rapid onset and offset of effect; however, its indication is limited to P2Y12 antagonist-naïve patients undergoing percutaneous coronary intervention. Two novel P2Y12 receptor antagonists are currently in clinical development, namely vicagrel and selatogrel. Vicagrel is an analog of clopidogrel with enhanced and more efficient formation of its active metabolite. Selatogrel is characterized by a rapid onset of action following subcutaneous administration and developed for early treatment of a suspected acute myocardial infarction. This review article describes the clinical pharmacology profile of marketed P2Y12 receptor antagonists and those under development focusing on pharmacokinetic, pharmacodynamic, and drug-drug interaction liability.
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Affiliation(s)
- Uta Schilling
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland
| | - Mike Ufer
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland
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Pickett SJ, Levine GN, Jneid H, Bhatt DL, Nambi V. Is There an Optimal Antiplatelet Strategy after Gastrointestinal Bleeding in Patients with Coronary Artery Disease? Cardiology 2021; 146:668-677. [PMID: 34521081 DOI: 10.1159/000517051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 05/04/2021] [Indexed: 11/19/2022]
Abstract
Gastrointestinal bleeding after percutaneous coronary intervention (PCI) is a not too uncommon clinical situation and is associated with high morbidity and mortality. After initial treatment, a number of clinical decisions must be made weighing the risks of ischemic events and future bleeding. In particular, healthcare providers must carefully balance the effectiveness of antiplatelet therapy in the secondary prevention of coronary events, primarily future spontaneous myocardial infarction and stent thrombosis, against the risk of major, most commonly gastrointestinal bleeding. The first question is whether a dual antiplatelet therapy strategy is required or if a single antiplatelet agent will suffice. Then, if a single antiplatelet agent is adequate, which agent should be continued. Although there is some guidance to answer some of these questions, there are inadequate evidence-based data for others. Below, we review the various considerations and summarize our approach and rationale to manage patients who had gastrointestinal bleeding after PCI.
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Affiliation(s)
- Stephen J Pickett
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA,
| | - Glenn N Levine
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Hani Jneid
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Vijay Nambi
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA
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10
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Effectiveness of Different P2Y12 Inhibitors on Coronary Flow in Patients with ST-Elevation Myocardial Infarction. JOURNAL OF CARDIOVASCULAR EMERGENCIES 2020. [DOI: 10.2478/jce-2020-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Background: ST-segment elevation myocardial infarction (STEMI) is a clinical syndrome with high mortality. The main purpose of STEMI treatment is to achieve optimal revascularization for tissue perfusion. Besides the innovations in revascularization strategies, developments in antithrombotic therapy resulted in a significant reduction in STEMI-related mortality. Reperfusion can be demonstrated by resolution of ST-segment elevation (STR), TIMI frame count (TFC), and myocardial blush grade (MBG). Aim of the study: In our study, we investigated the effects of P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor on reperfusion parameters such as TFC, MBG, and STR, after primary percutaneous coronary intervention (pPCI) in STEMI.
Material and Methods: The study was a retrospective analysis of STEMI patients who underwent successful pPCI. A total of 120 patients were included in the study as 3 equal groups according to the type of P2Y12 inhibitor administered in loading dose in the acute phase, and reperfusion parameters were compared between the groups.
Results: There was no statistically significant difference between the groups in terms of baseline demographic, clinical, and angiographic parameters. Evaluation of reperfusion parameters indicated that STR, MBG, angina relief after pPCI and corrected TFC (cTFC) were significantly different between the groups (p <0.05). In post-hoc analysis, the percentage of change in STR, MBG, angina relief after pPCI, and cTFC was significantly higher in the prasugrel group (p <0.017).
Conclusion: In STEMI patients undergoing pPCI, the analysis of tissue level reperfusion parameters indicates a superior effect of prasugrel compared with other P2Y12 inhibitors used to achieve reperfusion.
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11
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Terrier J, Daali Y, Fontana P, Csajka C, Reny JL. Towards Personalized Antithrombotic Treatments: Focus on P2Y 12 Inhibitors and Direct Oral Anticoagulants. Clin Pharmacokinet 2020; 58:1517-1532. [PMID: 31250210 DOI: 10.1007/s40262-019-00792-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Oral anticoagulants and antiplatelet drugs are commonly prescribed to lower the risk of cardiovascular diseases, such as venous and arterial thrombosis, which represent the leading causes of mortality worldwide. A significant percentage of patients taking antithrombotics will nevertheless experience bleeding or recurrent ischemic events, and this represents a major public health issue. Cardiovascular medicine is now questioning the one-size-fits-all policy, and more personalized approaches are increasingly being considered. However, the available tools are currently limited and they are only moderately able to predict clinical events or have a significant impact on clinical outcomes. Predicting concentrations of antithrombotics in blood could be an effective means of personalization as they have been associated with bleeding and recurrent ischemia. Target concentration interventions could take advantage of physiologically based pharmacokinetic (PBPK) and population-based pharmacokinetic (POPPK) models, which are increasingly used in clinical settings and have attracted the interest of governmental regulatory agencies, to propose dosages adapted to specific population characteristics. These models have the benefit of combining parameters from different sources, such as experimental in vitro data and patients' demographic, genetic, and physiological in vivo data, to characterize the dose-concentration relationships of compounds of interest. As such, they can be used to predict individual drug exposure. In the near future, these models could therefore be a valuable means of predicting personalized antithrombotic blood concentrations and, hopefully, of preventing clinical non-response or bleeding in a given patient. Existing approaches for personalization of antithrombotic prescriptions will be reviewed using practical examples for P2Y12 inhibitors and direct oral anticoagulants. The review will additionally focus on the existing PBPK and POPPK models for these two categories of drugs. Lastly, we address potential scenarios for their implementation in clinics, along with the main limitations and challenges.
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Affiliation(s)
- Jean Terrier
- Division of General Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.,Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Youssef Daali
- Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.,Clinical Pharmacology and Toxicology Service, Anesthesiology, Pharmacology and Intensive Care Department, Geneva University Hospitals, Geneva, Switzerland
| | - Pierre Fontana
- Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Division of Angiology and Haemostasis, Geneva University Hospitals, Geneva, Switzerland
| | - Chantal Csajka
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
| | - Jean-Luc Reny
- Division of General Internal Medicine, Geneva University Hospitals, Geneva, Switzerland. .,Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland. .,Division of Internal Medicine and Rehabilitation, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.
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12
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Povsic TJ, Ohman EM, Roe MT, White J, Rockhold FW, Montalescot G, Cornel JH, Nicolau JC, Steg PG, James S, Bode C, Welsh RC, Plotnikov AN, Mundl H, Gibson CM. P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes. JAMA Cardiol 2020; 4:680-684. [PMID: 31141104 DOI: 10.1001/jamacardio.2019.1510] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Importance Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown. Objective To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial. Design, Setting, and Participants The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019. Interventions Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization. Main Outcomes and Measures Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected. Results Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated. Conclusions and Relevance Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach. Clinical Trial Registration ClinicalTrials.gov identifier: NCT02293395.
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Affiliation(s)
- Thomas J Povsic
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - E Magnus Ohman
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Matthew T Roe
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Jennifer White
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Frank W Rockhold
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Gilles Montalescot
- Sorbonne Université, ACTION Study Group, Institut de Cardiologie, Pitié-Salpêtrière Hospital, Paris, France
| | - Jan H Cornel
- Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar and Dutch Network for Cardiovascular Research, the Netherlands
| | - Jose C Nicolau
- Insituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - P Gabriel Steg
- DHU FIRE, Université Paris-Diderot, AP-HP and Inserm U-1148, Paris, France.,National Heart and Lung Institute Royal Brompton Hospital, Imperial College, London, England
| | - Stefan James
- Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
| | - Christoph Bode
- University of Freiburg, Faculty of Medicine, Internal Medicine III, Freiburg, Germany
| | - Robert C Welsh
- Mazankowski Alberta Heart Institute and University of Alberta, Edmonton, Alberta, Canada
| | | | | | - C Michael Gibson
- PERFUSE Study Group, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, Massachusetts
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13
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Wipplinger C, Griessenauer CJ. Commentary: Antiplatelet Therapy in Flow Diversion. Neurosurgery 2020; 86:E231-E233. [PMID: 31844900 DOI: 10.1093/neuros/nyz462] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 08/23/2019] [Indexed: 11/13/2022] Open
Affiliation(s)
| | - Christoph J Griessenauer
- Department of Neurosurgery and Neuroscience Institute, Geisinger, Danville, Pennsylvania.,Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria
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14
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Lauver DA, Kuszynski DS, Christian BD, Bernard MP, Teuber JP, Markham BE, Chen YE, Zhang H. DT-678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y 12 antagonists. Pharmacol Res Perspect 2019; 7:e00509. [PMID: 31372229 PMCID: PMC6658415 DOI: 10.1002/prp2.509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/02/2019] [Accepted: 07/03/2019] [Indexed: 12/22/2022] Open
Abstract
The novel clopidogrel conjugate, DT-678, is an effective inhibitor of platelets and thrombosis in preclinical studies. However, a comparison of the bleeding risk with DT-678 and currently approved P2Y12 antagonists has yet to be determined. The objective of this study was to evaluate the bleeding tendency of animals treated with clopidogrel, ticagrelor, and DT-678. Ninety-one New Zealand white rabbits were randomized to one of 13 treatment groups (n = 7). Platelet activation was assessed by flow cytometry and light transmission aggregometry before and after the administration of various doses of DT-678, clopidogrel, and ticagrelor. Tongue template bleeding times were also measured before and after drug treatment. Treatment with P2Y12 receptor antagonists caused a dose-dependent reduction in markers of platelet activation (P-selectin and integrin αIIbβ3) and aggregation in response to adenosine diphosphate stimulation. At the same doses required for platelet inhibition, clopidogrel and ticagrelor significantly prolonged bleeding times, while DT-678 did not. DT-678 and the FDA-approved P2Y12 antagonists clopidogrel and ticagrelor are effective inhibitors of platelet activation and aggregation. However, unlike clopidogrel and ticagrelor, DT-678 did not prolong bleeding times at equally effective antiplatelet doses. The results suggest a more favorable benefit/risk ratio for DT-678 and potential utility as part of a dual antiplatelet therapy regimen.
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Affiliation(s)
- Dale A. Lauver
- Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingMIUSA
| | - Dawn S. Kuszynski
- Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingMIUSA
| | - Barbara D. Christian
- Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingMIUSA
| | - Matthew P. Bernard
- Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingMIUSA
| | - James P. Teuber
- Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingMIUSA
| | | | - Yuqing E. Chen
- Diapin Therapeutics, LLCAnn ArborMIUSA
- Department of PharmacologyUniversity of MichiganAnn ArborMIUSA
| | - Haoming Zhang
- Department of PharmacologyUniversity of MichiganAnn ArborMIUSA
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15
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Keminer O, Windshügel B, Essmann F, Lee SML, Schiergens TS, Schwab M, Burk O. Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol 2019; 93:2247-2264. [PMID: 31312845 DOI: 10.1007/s00204-019-02495-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 06/17/2019] [Indexed: 11/28/2022]
Abstract
Prediction of drug interactions, based on the induction of drug disposition, calls for the identification of chemicals, which activate xenosensing nuclear receptors. Constitutive androstane receptor (CAR) is one of the major human xenosensors; however, the constitutive activity of its reference variant CAR1 in immortalized cell lines complicates the identification of agonists. The exclusively ligand-dependent isoform CAR3 represents an obvious alternative for screening of CAR agonists. As CAR3 is even more abundant in human liver than CAR1, identification of its agonists is also of pharmacological value in its own right. We here established a cellular high-throughput screening assay for CAR3 to identify ligands of this isoform and to analyse its suitability for identifying CAR ligands in general. Proof-of-concept screening of 2054 drug-like compounds at 10 µM resulted in the identification of novel CAR3 agonists. The CAR3 assay proved to detect the previously described CAR1 ligands in the screened libraries. However, we failed to detect CAR3-selective compounds, as the four novel agonists, which were selected for further investigations, all proved to activate CAR1 in different cellular and in vitro assays. In primary human hepatocytes, the compounds preferentially induced the expression of the prototypical CAR target gene CYP2B6. Failure to identify CAR3-selective compounds was investigated by molecular modelling, which showed that the isoform-specific insertion of five amino acids did not impact on the ligand binding pocket but only on heterodimerization with retinoid X receptor. In conclusion, we demonstrate here the usability of CAR3 for screening compound libraries for the presence of CAR agonists.
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Affiliation(s)
- Oliver Keminer
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Schnackenburgallee 114, 22525, Hamburg, Germany
| | - Björn Windshügel
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Schnackenburgallee 114, 22525, Hamburg, Germany.
| | - Frank Essmann
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.,University of Tübingen, Tübingen, Germany
| | - Serene M L Lee
- Biobank of the Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Tobias S Schiergens
- Biobank of the Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.,Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany
| | - Oliver Burk
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany. .,University of Tübingen, Tübingen, Germany.
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16
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In Vitro Assessment of Potential for CYP-Inhibition-Based Drug-Drug Interaction Between Vonoprazan and Clopidogrel. Eur J Drug Metab Pharmacokinet 2019; 44:217-227. [PMID: 30361928 DOI: 10.1007/s13318-018-0521-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES It was recently proposed that CYP-mediated drug-drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work. METHODS Reversible inhibition studies focusing on the effects of vonoprazan on CYP marker activities and the formation of the [14C]clopidogrel metabolite H4 were conducted with and without pre-incubation using HLMs. Time-dependent inhibition (TDI) kinetics were also measured. RESULTS It was found that vonoprazan is not a significant direct inhibitor of any CYP isoforms (IC50 ≥ 16 μM), but shows the potential for TDI of CYP2B6, CYP2C19, and CYP3A4/5. This TDI was weaker than the inhibition induced by the corresponding reference inhibitors ticlopidine, esomeprazole, and verapamil, based on the measured potencies (kinact/KI ratio and the R2 value). In a more direct in vitro experiment, vonoprazan levels of up to 10 µM (a 100-fold higher concentration than the plasma Cmax of 75.9 nM after taking 20 mg once daily for 7 days) did not suppress the formation of the active metabolite H4 or other oxidative metabolites of [14C]clopidogrel in a reversible or time-dependent manner. Additionally, an assessment of clinical trials and post-marketing data suggested no evidence of a DDI between vonoprazan and clopidogrel. CONCLUSIONS The body of evidence shows that the pharmacodynamic DDI reported between vonoprazan and clopidogrel is unlikely to be caused by the inhibition of CYP2B6, CYP2C19, or CYP3A4/5 by vonoprazan.
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17
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Tatarunas V, Kupstyte-Kristapone N, Norvilaite R, Tamakauskas V, Skipskis V, Audrone V, Jurgaityte J, Stuoka M, Lesauskaite V. The impact of CYP2C19 and CYP4F2 variants and clinical factors on treatment outcomes during antiplatelet therapy. Pharmacogenomics 2019; 20:483-492. [PMID: 31124413 DOI: 10.2217/pgs-2018-0178] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Aim: The aim of this study was to determine the impact of genetic and nongenetic factors on treatment outcomes in patients receiving dual antiplatelet therapy after percutaneous coronary intervention and stent implantation. Materials & methods: Patients (n = 628) used clopidogrel or ticagrelor for at least 1 week before platelet aggregation test. Results: Multivariate binary regression analysis demonstrated that aspirin use and CYP4F2 T allele significantly increased odds for bleeding in clopidogrel users (OR: 2.488, 95% CI: 1.452-4.265; p = 0.001 and OR: 1.573, 95% CI: 1.066-2.320; respectively; p = 0.022). CYP4F2 T allele significantly increased odds for bleeding in ticagrelor users (OR: 8.270, 95% CI: 3.917-17.462; p < 0.001). Conclusion: Aspirin use and CYP4F2 T allele were significantly associated with bleeding during dual antiplatelet therapy.
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Affiliation(s)
- Vacis Tatarunas
- Institute of Cardiology of Lithuanian University of Health Sciences, Sukileliu 17, Kaunas, LT 50009, Lithuania
| | - Nora Kupstyte-Kristapone
- Institute of Cardiology of Lithuanian University of Health Sciences, Sukileliu 17, Kaunas, LT 50009, Lithuania.,Department of Cardiology of Lithuanian University of Health Sciences, Eiveniu 2, LT 50009, Kaunas, Lithuania.,Heart & Vascular Center of Republican Siauliai hospital, V. Kudirkos g. 99, 76231 Šiauliai, Lithuania
| | - Rita Norvilaite
- Lithuanian University of Health Sciences, A Mickeviciaus 9, LT 44307, Kaunas, Lithuania
| | - Vytenis Tamakauskas
- Institute of Cardiology of Lithuanian University of Health Sciences, Sukileliu 17, Kaunas, LT 50009, Lithuania.,Heart & Vascular Center of Republican Siauliai hospital, V. Kudirkos g. 99, 76231 Šiauliai, Lithuania
| | - Vilius Skipskis
- Institute of Cardiology of Lithuanian University of Health Sciences, Sukileliu 17, Kaunas, LT 50009, Lithuania
| | - Veikutiene Audrone
- Institute of Cardiology of Lithuanian University of Health Sciences, Sukileliu 17, Kaunas, LT 50009, Lithuania.,Department of Cardiac, Thoracic & Vascular Surgery, Eiveniu 2, LT 50009, Kaunas, Lithuania
| | - Julija Jurgaityte
- Lithuanian University of Health Sciences, A Mickeviciaus 9, LT 44307, Kaunas, Lithuania
| | - Mantvydas Stuoka
- Lithuanian University of Health Sciences, A Mickeviciaus 9, LT 44307, Kaunas, Lithuania
| | - Vaiva Lesauskaite
- Institute of Cardiology of Lithuanian University of Health Sciences, Sukileliu 17, Kaunas, LT 50009, Lithuania
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18
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Liu C, Zhang Y, Chen W, Lu Y, Li W, Liu Y, Lai X, Gong Y, Liu X, Li Y, Chen X, Li X, Sun H, Yang J, Zhong D. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing. Eur J Pharm Sci 2019; 127:151-160. [DOI: 10.1016/j.ejps.2018.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 08/31/2018] [Accepted: 10/11/2018] [Indexed: 12/18/2022]
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19
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Imai S, Ichikawa T, Sugiyama C, Nonaka K, Yamada T. Contribution of Human Liver and Intestinal Carboxylesterases to the Hydrolysis of Selexipag In Vitro. J Pharm Sci 2018; 108:1027-1034. [PMID: 30267780 DOI: 10.1016/j.xphs.2018.09.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 09/07/2018] [Accepted: 09/14/2018] [Indexed: 02/01/2023]
Abstract
In liver microsomes, selexipag (NS-304; ACT-293987) mainly undergoes hydrolytic removal of the sulfonamide moiety by carboxylesterase 1 (CES1) to yield the pharmacologically active metabolite MRE-269 (ACT-333679). However, it is not known how much CES in the liver and intestine contributes to the hydrolysis of selexipag or how selexipag is metabolized in the intestine, including by hydrolysis. To obtain a better understanding of selexipag metabolism in humans, we determined the percentage contribution of CES1 and carboxylesterase 2 (CES2) to the hydrolysis of selexipag and 7 of its analogs with different sulfonamide moieties and evaluated its nonhydrolytic metabolism in human liver microsomes and human intestinal microsomes (HIMS). For selexipag, the percentage contributions of CES1 and CES2 in human liver microsomes were 77.0% and 9.99%, respectively, while the percentage contribution of CES2 in HIMS was 100%. In HIMS, the rate of hydrolysis of selexipag was the lowest among the compounds tested, and no difference between the presence and absence of nicotinamide adenine dinucleotide phosphate was noted. We infer from these results that selexipag is likely to be hydrolyzed by CES2 as well as CES1, and only selexipag itself and the MRE-269 produced by hydrolysis in the intestine would be absorbed after oral administration.
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Affiliation(s)
- Shunji Imai
- Pharmacokinetics and Safety Assessment Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, Kyoto, Japan.
| | - Tomohiko Ichikawa
- Pharmacokinetics and Safety Assessment Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, Kyoto, Japan
| | - Chihiro Sugiyama
- Pharmacokinetics and Safety Assessment Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, Kyoto, Japan
| | - Kiyoko Nonaka
- Pharmacokinetics and Safety Assessment Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, Kyoto, Japan
| | - Tetsuhiro Yamada
- Pharmacokinetics and Safety Assessment Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, Kyoto, Japan
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20
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Itkonen MK, Tornio A, Lapatto-Reiniluoto O, Neuvonen M, Neuvonen PJ, Niemi M, Backman JT. Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel. Clin Pharmacol Ther 2018; 105:219-228. [PMID: 29696643 PMCID: PMC6585621 DOI: 10.1002/cpt.1099] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 04/23/2018] [Indexed: 12/11/2022]
Abstract
Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0‐∞ of dasabuvir 4.7‐fold; range 2.0–10.1‐fold (P = 8·10−7), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC0‐∞ 3.9‐fold; range 2.1–7.9‐fold (P = 2·10−6), compared with ritonavir alone. Ritonavir decreased the AUC0‐4h of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.
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Affiliation(s)
- Matti K Itkonen
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Aleksi Tornio
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Outi Lapatto-Reiniluoto
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko Neuvonen
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Pertti J Neuvonen
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Janne T Backman
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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21
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Cameron SJ, Mix DS, Ture SK, Schmidt RA, Mohan A, Pariser D, Stoner MC, Shah P, Chen L, Zhang H, Field DJ, Modjeski KL, Toth S, Morrell CN. Hypoxia and Ischemia Promote a Maladaptive Platelet Phenotype. Arterioscler Thromb Vasc Biol 2018; 38:1594-1606. [PMID: 29724818 PMCID: PMC6023774 DOI: 10.1161/atvbaha.118.311186] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 04/17/2018] [Indexed: 12/26/2022]
Abstract
Supplemental Digital Content is available in the text. Objective— Reduced blood flow and tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We, therefore, sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions. Approach and Results— In a cohort of patients with metabolic and peripheral artery disease, platelet activity was enhanced, and inhibition with oral antiplatelet agents was impaired compared with platelets from control subjects, suggesting a difference in platelet phenotype caused by the disease. Isolated murine and human platelets exposed to reduced oxygen (hypoxia chamber, 5% O2) had increased expression of some proteins that augment platelet activation compared with platelets in normoxic conditions (21% O2). Using a murine model of critical limb ischemia, platelet activity was increased even 2 weeks postsurgery compared with sham surgery mice. This effect was partly inhibited in platelet-specific ERK5 (extracellular regulated protein kinase 5) knockout mice. Conclusions— These findings suggest that ischemic disease changes the platelet phenotype and alters platelet agonist responses because of changes in the expression of signal transduction pathway proteins. Platelet phenotype and function should, therefore, be better characterized in ischemic and hypoxic diseases to understand the benefits and limitations of antiplatelet therapy.
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Affiliation(s)
- Scott J Cameron
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.) .,Division of Cardiology, Department of Medicine (S.J.C., C.N.M.)
| | - Doran S Mix
- Division of Vascular Surgery, Department of Surgery (D.S.M., M.C.S., S.T.), University of Rochester School of Medicine, NY
| | - Sara K Ture
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.)
| | - Rachel A Schmidt
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.)
| | - Amy Mohan
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.)
| | - Daphne Pariser
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.)
| | - Michael C Stoner
- Division of Vascular Surgery, Department of Surgery (D.S.M., M.C.S., S.T.), University of Rochester School of Medicine, NY
| | - Punit Shah
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD (P.S., L.C., H.Z.)
| | - Lijun Chen
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD (P.S., L.C., H.Z.)
| | - Hui Zhang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD (P.S., L.C., H.Z.)
| | - David J Field
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.)
| | - Kristina L Modjeski
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.)
| | - Sandra Toth
- Division of Vascular Surgery, Department of Surgery (D.S.M., M.C.S., S.T.), University of Rochester School of Medicine, NY
| | - Craig N Morrell
- From the Aab Cardiovascular Research Institute (S.J.C., S.K.T., R.A.S., A.M., D.P., D.J.F., K.L.M., C.N.M.).,Division of Cardiology, Department of Medicine (S.J.C., C.N.M.)
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22
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Griessenauer CJ, Jain A, Enriquez-Marulanda A, Gupta R, Adeeb N, Moore JM, Grassi SA, Dalal SS, Ogilvy CS, Thomas AJ, Schirmer CM. Pharmacy-Mediated Antiplatelet Management Protocol Compared to One-time Platelet Function Testing Prior to Pipeline Embolization of Cerebral Aneurysms: A Propensity Score-Matched Cohort Study. Neurosurgery 2018; 84:673-679. [DOI: 10.1093/neuros/nyy091] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/22/2018] [Indexed: 11/12/2022] Open
Affiliation(s)
- Christoph J Griessenauer
- Department of Neurosurgery, Geisinger Health, Danville, Pennsylvania
- Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria
- Department of Neurosurgery, Paracelsus Medical University, Salzburg, Austria
| | - Abhi Jain
- Department of Neurosurgery, Geisinger Health, Danville, Pennsylvania
- Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania
| | | | - Raghav Gupta
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Nimer Adeeb
- Department of Neurosurgery, Louisiana State University, Shreveport, Louisiana
| | - Justin M Moore
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Stacey A Grassi
- Department of Pharmacy, Geisinger Health, Danville, Pennsylvania
| | - Shamsher S Dalal
- Department of Radiology, Geisinger Health, Danville, Pennsylvania
| | - Christopher S Ogilvy
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Ajith J Thomas
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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23
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Bjerre D, Berg Rasmussen H, INDICES Consortium T. Novel approach for CES1 genotyping: integrating single nucleotide variants and structural variation. Pharmacogenomics 2018; 19:349-359. [DOI: 10.2217/pgs-2016-0145] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Aim: Development of a specific procedure for genotyping of CES1A1 (CES1) and CES1A2, a hybrid of CES1A1 and the pseudogene CES1P1. Materials & methods: The number of CES1A1 and CES1A2 copies and that of CES1P1 were determined using real-time PCR. Long range PCRs followed by secondary PCRs allowed sequencing of single nucleotide variants in CES1A1 and CES1A2. Results & conclusion: A procedure consisting of two main steps was developed. Its first main step, the copy number determination, informed about presence of CES1A2 . This information enabled choice of PCR in the second main step, which selectively amplified CES1A1 and, if present, also CES1A2, for subsequent sequencing. Examination of 501 DNA samples suggested that our procedure is specific with potential for personalization of drug treatments.
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Affiliation(s)
- Ditte Bjerre
- Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, DK-4000 Roskilde, Denmark
| | - Henrik Berg Rasmussen
- Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, DK-4000 Roskilde, Denmark
- Department of Science and Environment, Roskilde University, DK-4000 Roskilde, Denmark
| | - The INDICES Consortium
- A list of the members of the consortium has been included in the accompanying this publication
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24
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Development and validation of a sensitive and rapid UHPLC–MS/MS method for the simultaneous quantification of the common active and inactive metabolites of vicagrel and clopidogrel in human plasma. J Pharm Biomed Anal 2018; 149:394-402. [DOI: 10.1016/j.jpba.2017.11.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 11/01/2017] [Indexed: 11/21/2022]
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25
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Kahma H, Filppula AM, Neuvonen M, Tarkiainen EK, Tornio A, Holmberg MT, Itkonen MK, Finel M, Neuvonen PJ, Niemi M, Backman JT. Clopidogrel Carboxylic Acid Glucuronidation is Mediated Mainly by UGT2B7, UGT2B4, and UGT2B17: Implications for Pharmacogenetics and Drug-Drug Interactions . Drug Metab Dispos 2018; 46:141-150. [PMID: 29138287 DOI: 10.1124/dmd.117.078162] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 11/11/2017] [Indexed: 01/04/2023] Open
Abstract
The antiplatelet drug clopidogrel is metabolized to an acyl-β-d-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-β-d-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLMs and HIMs, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers. UGT2B7 and UGT2B17 exhibited the greatest level of clopidogrel carboxylic acid glucuronidation activities, with a CLint,u of 2.42 and 2.82 µl⋅min-1⋅mg-1, respectively. Of other enzymes displaying activity (UGT1A3, UGT1A9, UGT1A10-H, and UGT2B4), UGT2B4 (CLint,u 0.51 µl⋅min-1⋅mg-1) was estimated to contribute significantly to the hepatic clearance. Nonselective UGT2B inhibitors strongly inhibited clopidogrel acyl-β-d-glucuronide formation in HLMs and HIMs. The UGT2B17 inhibitor imatinib and the UGT2B7 and UGT1A9 inhibitor mefenamic acid inhibited clopidogrel carboxylic acid glucuronidation in HIMs and HLMs, respectively. Incubation of clopidogrel carboxylic acid in HLMs with UDPGA and NADPH resulted in strong inhibition of CYP2C8 activity. In healthy volunteers, the UGT2B17*2 deletion allele was associated with a 10% decrease per copy in the plasma clopidogrel acyl-β-d-glucuronide to clopidogrel carboxylic acid area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4) ratio (P < 0.05). To conclude, clopidogrel carboxylic acid is metabolized mainly by UGT2B7 and UGT2B4 in the liver and by UGT2B17 in the small intestinal wall. The formation of clopidogrel acyl-β-d-glucuronide is impaired in carriers of the UGT2B17 deletion. These findings may have implications regarding the intracellular mechanisms leading to CYP2C8 inactivation by clopidogrel.
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Affiliation(s)
- Helinä Kahma
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Anne M Filppula
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Mikko Neuvonen
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - E Katriina Tarkiainen
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Aleksi Tornio
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Mikko T Holmberg
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Matti K Itkonen
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Moshe Finel
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Pertti J Neuvonen
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Mikko Niemi
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
| | - Janne T Backman
- Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, and Helsinki University Hospital (H.K., A.M.F., M.Ne., E.K.T., A.T., M.T.H., M.K.I., P.J.N., M.Ni., J.T.B.) and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki (M.F.), Helsinki, Finland
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26
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Fefer P, Matetzky S. The genetic basis of platelet responsiveness to clopidogrel. Thromb Haemost 2017; 106:203-10. [DOI: 10.1160/th11-04-0228] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Accepted: 06/30/2011] [Indexed: 01/06/2023]
Abstract
SummaryClopidogrel reduces ischaemic complications in a wide range of patients with coronary artery disease. However, there is much inter-individual variation in clopidogrel-induced platelet inhibition, and a substantial proportion of patients will exhibit non-responsiveness to clopidogrel. Multiple studies have demonstrated an association between the presence of genetic polymorphisms associated with suboptimal clopidogrel-active metabolite generation, decreased platelet responsiveness, and adverse clinical outcomes. However, it is not clear to what extent the genetic polymorphisms account for the observed variability in response to clopidogrel. In this review we provide a critical summary of the available evidence linking genetic factors with response to clopidogrel, and discuss the clinical implications of this association.
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27
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Jiang J, Chen X, Zhong D. Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans. Front Pharmacol 2017; 8:846. [PMID: 29209217 PMCID: PMC5701912 DOI: 10.3389/fphar.2017.00846] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 11/06/2017] [Indexed: 11/26/2022] Open
Abstract
Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine. This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxo-clopidogrel production from vicagrel in human intestine. In vitro hydrolytic kinetics were determined in human intestine microsomes and recombinant human CES and AADAC. The calculated contribution of CES2 and AADAC to vicagrel hydrolysis was 44.2 and 53.1% in human intestine, respectively. The AADAC-selective inhibitors vinblastine and eserine effectively inhibited vicagrel hydrolysis in vitro. In addition to CES2, human intestine AADAC was involved in vicagrel hydrolytic activation before it entered systemic circulation. In addition, simvastatin efficiently inhibited the production of both 2-oxo-clopidogrel and active H4; further clinical trials are needed to determine whether the hydrolytic activation of vicagrel is influenced by coadministration with simvastatin. This study deepens the understanding of the bioactivation and metabolism properties of vicagrel in humans, which can help further understand the bioactivation mechanism of vicagrel and the variations in the treatment responses to vicagrel and clopidogrel.
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Affiliation(s)
- Jinfang Jiang
- State Key Laboratory of Drug Research, Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyan Chen
- State Key Laboratory of Drug Research, Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Dafang Zhong
- State Key Laboratory of Drug Research, Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
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28
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Wang X, Rida N, Shi J, Wu AH, Bleske BE, Zhu HJ. A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms. Drug Metab Dispos 2017; 45:1149-1155. [PMID: 28838926 PMCID: PMC5637814 DOI: 10.1124/dmd.117.077669] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 08/21/2017] [Indexed: 12/11/2022] Open
Abstract
Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In this study, we comprehensively examined the functions of CES1 nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include CES1 nsSNPs with a minor allele frequency >0.5% in a given population or located in close proximity to the CES1 active site. Five nsSNPs, including L40Ter (rs151291296), G142E (rs121912777), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), were loss-of-function variants for metabolizing the CES1 substrates clopidogrel, enalapril, and sacubitril. In addition, A158V (rs202121317), R199H (rs2307243), E220G (rs200707504), and T290M (rs202001817) decreased CES1 activity to a lesser extent in a substrate-dependent manner. Several nsSNPs, includingL40Ter (rs151291296), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), significantly reduced CES1 protein and/or mRNA expression levels in the transfected cells. Functions of the common nonsynonymous haplotypes D203E-A269S and S75N-D203E-A269S were evaluated using cells stably expressing the haplotypes and a large set of the human liver. Neither CES1 expression nor activity was affected by the two haplotypes. In summary, this study revealed several functional nsSNPs with impaired activity on the metabolism of CES1 substrate drugs. Clinical investigations are warranted to determine whether these nsSNPs can serve as biomarkers for the prediction of therapeutic outcomes of drugs metabolized by CES1.
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Affiliation(s)
- Xinwen Wang
- Department of Clinical Pharmacy (X.W., N.R., J.S., H.-J.Z.) and Cardiovascular Center (A.H.W.), University of Michigan, Ann Arbor, Michigan; and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Nada Rida
- Department of Clinical Pharmacy (X.W., N.R., J.S., H.-J.Z.) and Cardiovascular Center (A.H.W.), University of Michigan, Ann Arbor, Michigan; and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Jian Shi
- Department of Clinical Pharmacy (X.W., N.R., J.S., H.-J.Z.) and Cardiovascular Center (A.H.W.), University of Michigan, Ann Arbor, Michigan; and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Audrey H Wu
- Department of Clinical Pharmacy (X.W., N.R., J.S., H.-J.Z.) and Cardiovascular Center (A.H.W.), University of Michigan, Ann Arbor, Michigan; and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Barry E Bleske
- Department of Clinical Pharmacy (X.W., N.R., J.S., H.-J.Z.) and Cardiovascular Center (A.H.W.), University of Michigan, Ann Arbor, Michigan; and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Hao-Jie Zhu
- Department of Clinical Pharmacy (X.W., N.R., J.S., H.-J.Z.) and Cardiovascular Center (A.H.W.), University of Michigan, Ann Arbor, Michigan; and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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29
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Xiao FY, Luo JQ, Liu M, Chen BL, Cao S, Liu ZQ, Zhou HH, Zhou G, Zhang W. Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients. Sci Rep 2017; 7:7244. [PMID: 28775293 PMCID: PMC5543069 DOI: 10.1038/s41598-017-07736-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. The effects of CES1 S75N (rs2307240,C>T) on clopidogrel response among 851 acute coronary syndrome patients who came from the north, central and south of China were studied. The occurrence ratios of each endpoint in the CC group were significantly higher than in the CT + TT group for cerebrovascular events (14% vs 4.8%, p < 0.001, OR = 0.31), acute myocardial infarction (15.1% vs 6.1%, p < 0.001, OR = 0.37) and unstable angina (62.8% vs 37.7%, p < 0.001, OR = 0.36). The results showed that there was a significant association between CES1 S75N (rs2307240) and the outcome of clopidogrel therapy. Moreover, the frequency of the T allele of rs2307240 in acute coronary syndrome patients (MAF = 0.22) was more than four times higher than that in the general public (MAF = 0.05).
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Affiliation(s)
- Fei-Yan Xiao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China
| | - Jian-Quan Luo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China
| | - Min Liu
- Department of cardiovascular, Zhengzhou central hospital, Zhengzhou University, Zhengzhou, China
| | - Bi-Lian Chen
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
| | - Shan Cao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China
| | - Gan Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
- National institution of drug clinical trial, Xiangya Hospital, Central South University, Changsha, China.
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
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30
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Tatarunas V, Kupstyte N, Zaliunas R, Giedraitiene A, Lesauskaite V. The impact of clinical and genetic factors on ticagrelor and clopidogrel antiplatelet therapy. Pharmacogenomics 2017; 18:969-979. [DOI: 10.2217/pgs-2017-0070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To determine clinically significant factors which may alter the effect of dual antiplatelet therapy with aspirin and ticagrelor or clopidogrel in patients who had undergone percutaneous coronary intervention and stent implantation. Materials & methods: The study included 378 patients. All the patients had undergone percutaneous coronary intervention and stent implantation. Platelet aggregation and genotyping for CYP2C19 *2 (rs4244285) and CYP4F2 (rs2108622, rs1558139, rs3093135 and rs2074902) was performed. Results: Significantly lower platelet aggregation values (%agr) were detected in ticagrelor users who carried CYP4F2 rs3093135 TT variant (14.67 ± 5.07%agr) versus AA (22.88 ± 6.30%agr), p = 0.0004, or AT (20.56 ± 6.51%agr), p = 0.0126. Conclusion: Results of the current study showed that CYP4F2 rs3093135 TT variant carriers had a higher antiplatelet effect of ticagrelor, and more frequently had nonprocedural bleeding during ticagrelor therapy, as compared with AA and AT variant carriers.
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Affiliation(s)
- Vacis Tatarunas
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 17, Kaunas LT 50009, Lithuania
| | - Nora Kupstyte
- Department of Cardiology, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas LT 50009, Lithuania
| | - Remigijus Zaliunas
- Department of Cardiology, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas LT 50009, Lithuania
| | - Agne Giedraitiene
- Department of Microbiology, Lithuanian University of Health Sciences, A. Mickeviciaus 9, Kaunas LT 44307, Lithuania
| | - Vaiva Lesauskaite
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 17, Kaunas LT 50009, Lithuania
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31
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Zhang Y, Peti-Peterdi J, Brandes AU, Riquier-Brison A, Carlson NG, Müller CE, Ecelbarger CM, Kishore BK. Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice. Purinergic Signal 2017; 13:239-248. [PMID: 28233082 PMCID: PMC5432483 DOI: 10.1007/s11302-017-9555-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 01/23/2017] [Indexed: 12/17/2022] Open
Abstract
Previously, we localized ADP-activated P2Y12 receptor (R) in rodent kidney and showed that its blockade by clopidogrel bisulfate (CLPD) attenuates lithium (Li)-induced nephrogenic diabetes insipidus (NDI). Here, we evaluated the effect of prasugrel (PRSG) administration on Li-induced NDI in mice. Both CLPD and PRSG belong to the thienopyridine class of ADP receptor antagonists. Groups of age-matched adult male B6D2 mice (N = 5/group) were fed either regular rodent chow (CNT), or with added LiCl (40 mmol/kg chow) or PRSG in drinking water (10 mg/kg bw/day) or a combination of LiCl and PRSG for 14 days and then euthanized. Water intake and urine output were determined and blood and kidney tissues were collected and analyzed. PRSG administration completely suppressed Li-induced polydipsia and polyuria and significantly prevented Li-induced decreases in AQP2 protein abundance in renal cortex and medulla. However, PRSG either alone or in combination with Li did not have a significant effect on the protein abundances of NKCC2 or NCC in the cortex and/or medulla. Immunofluorescence microscopy revealed that PRSG administration prevented Li-induced alterations in cellular disposition of AQP2 protein in medullary collecting ducts. Serum Li, Na, and osmolality were not affected by the administration of PRSG. Similar to CLPD, PRSG administration had no effect on Li-induced increase in urinary Na excretion. However, unlike CLPD, PRSG did not augment Li-induced increase in urinary arginine vasopressin (AVP) excretion. Taken together, these data suggest that the pharmacological inhibition of P2Y12-R by the thienopyridine group of drugs may potentially offer therapeutic benefits in Li-induced NDI.
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Affiliation(s)
- Yue Zhang
- Department of Internal Medicine and Center on Aging, University of Utah Health Sciences Center, Veterans Affairs Salt Lake City, Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT, 84148, USA
| | - János Peti-Peterdi
- Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, University of Southern California, 1501 San Pablo Street, ZNI 313, Los Angeles, CA, 90033, USA
| | - Anna U Brandes
- Department of Internal Medicine and Center on Aging, University of Utah Health Sciences Center, Veterans Affairs Salt Lake City, Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT, 84148, USA
| | - Anne Riquier-Brison
- Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, University of Southern California, 1501 San Pablo Street, ZNI 313, Los Angeles, CA, 90033, USA
| | - Noel G Carlson
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany
| | - Christa E Müller
- Depatment of Neurobiology and Anatomy and Center on Aging, University of Utah Health Sciences Center, Geriatric Research, Education, and Clinical Center (GRECC) Veterans Affairs Salt Lake City Health Care System, 500 Foothill Drive (151B), Salt Lake City, UT, 84148, USA
| | - Carolyn M Ecelbarger
- Department of Medicine, Center for the Study of Sex Differences in Health, Aging, and Disease, Georgetown University, 4000 Reservoir Road NW Bldg D, Rm 392, Washington, DC, 20057, USA
| | - Bellamkonda K Kishore
- Department of Internal Medicine and Center on Aging, University of Utah Health Sciences Center, Veterans Affairs Salt Lake City, Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT, 84148, USA.
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Samant S, Jiang XL, Peletier LA, Shuldiner AR, Horenstein RB, Lewis JP, Lesko LJ, Schmidt S. Identifying clinically relevant sources of variability: The clopidogrel challenge. Clin Pharmacol Ther 2016; 101:264-273. [DOI: 10.1002/cpt.459] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 08/10/2016] [Accepted: 08/12/2016] [Indexed: 12/14/2022]
Affiliation(s)
- S Samant
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology; University of Florida at Lake Nona; Orlando Florida USA
| | - XL Jiang
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology; University of Florida at Lake Nona; Orlando Florida USA
| | - LA Peletier
- Mathematical Institute; Leiden University; PB 9512 2300 RA Leiden The Netherlands
| | - AR Shuldiner
- Division of Endocrinology, Diabetes and Nutrition; University of Maryland School of Medicine; Baltimore Maryland USA
| | - RB Horenstein
- Division of Endocrinology, Diabetes and Nutrition; University of Maryland School of Medicine; Baltimore Maryland USA
| | - JP Lewis
- Division of Endocrinology, Diabetes and Nutrition; University of Maryland School of Medicine; Baltimore Maryland USA
| | - LJ Lesko
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology; University of Florida at Lake Nona; Orlando Florida USA
| | - S Schmidt
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology; University of Florida at Lake Nona; Orlando Florida USA
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Qiu ZX, Gao WC, Dai Y, Zhou SF, Zhao J, Lu Y, Chen XJ, Li N. Species Comparison of Pre-systemic Bioactivation of Vicagrel, a New Acetate Derivative of Clopidogrel. Front Pharmacol 2016; 7:366. [PMID: 27774067 PMCID: PMC5054534 DOI: 10.3389/fphar.2016.00366] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 09/26/2016] [Indexed: 11/18/2022] Open
Abstract
Previously we have found vicagrel, a new acetate derivative of clopidogrel, underwent hydrolysis to 2-oxo-clopidogrel and subsequent conversions to its pharmacological active metabolite (AM) and inactive carboxylic acid metabolite (CAM). This study demonstrated the interspecies differences of the vicagrel bioactivation by comparing the critical vicagrel metabolites formation in rats, dogs and human. The pharmacokinetic studies with rats and dogs were conducted after intragastric administration of vicagrel, followed by in vitro metabolism investigation in venous system, intestinal/hepatic microsomes from rats, dogs and human. An obvious disparity was observed in system exposure to AM (99.0 vs. 635.1 μg⋅h/L, p < 0.05) and CAM (10119 vs. 2634 μg⋅h/L, p < 0.05) in rats and dogs. It was shown that the cleavage of vicagrel was almost completed in intestine with great different clearance (53.28 vs. 3.643 L⋅h-1⋅kg-1, p < 0.05) in rats and dogs. With no further hydrolysis to CAM, the greatest clearance of AM (3.26 mL⋅h-1⋅kg-1) was found in dog intestine. In rat plasma, 2-oxo-clopidogrel was much more extensively hydrolyzed to CAM than in dog and human. Albeit similar hydrolysis clearance and AM production was observed among hepatic microsomes of the three species, the production velocity of CAM ranked highest in dogs (7.55 pmol/min/mg protein). Therefore, the unconformity of AM and CAM exposure cross species mainly came from the metabolism of 2-oxo-clopidogrel associated largely with tissue specificity and interspecies differences of esterases. In human, the pharmacokinetics of vicagrel might be more optimistic due to less inactivation hydrolysis before reaching liver.
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Affiliation(s)
- Zhi-Xia Qiu
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University Nanjing, China
| | - Wen-Chao Gao
- Clinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing, China
| | - Yu Dai
- Clinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing, China
| | - Su-Feng Zhou
- Clinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing, China
| | - Jie Zhao
- Clinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing, China
| | - Yang Lu
- Clinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing, China
| | - Xi-Jing Chen
- Clinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing, China
| | - Ning Li
- Clinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityNanjing, China; National Experimental Teaching Demonstration Center of Pharmacy, China Pharmaceutical UniversityNanjing, China
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Zhang H, Lauver DA, Wang H, Sun D, Hollenberg PF, Chen YE, Osawa Y, Eitzman DT. Significant Improvement of Antithrombotic Responses to Clopidogrel by Use of a Novel Conjugate as Revealed in an Arterial Model of Thrombosis. J Pharmacol Exp Ther 2016; 359:11-7. [PMID: 27511819 PMCID: PMC5034710 DOI: 10.1124/jpet.116.236034] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 08/09/2016] [Indexed: 11/22/2022] Open
Abstract
Clopidogrel is a prodrug that requires bioactivation by cytochrome P450 (P450) enzymes to a pharmacologically active metabolite for antiplatelet action. The clinical limitations of clopidogrel are in large part due to its poor pharmacokinetics resulting from inefficient bioactivation by P450s. In this study, we determined the pharmacokinetics and pharmacodynamics of a novel conjugate of clopidogrel, referred to as ClopNPT, in animal models and we evaluated its potential to overcome the limitations of clopidogrel. Results from pharmacokinetic (PK) studies showed that ClopNPT released the active metabolite with a time to maximal plasma concentration of <5 minutes in C57BL/6 mice after either oral or intravenous administration, and plasma concentrations of the active metabolite reached Cmax values of 1242 and 1100 ng/ml after a 10-mg/kg oral dose and a 5-mg/kg intravenous dose, respectively. Furthermore, ClopNPT was highly effective in preventing arterial thrombosis in rabbits and mice after vascular injuries. Formation of occlusive thrombi was prevented by ClopNPT at the 1-mg/kg dose with no significant increase in tongue bleeding time, whereas clopidogrel was ineffective at the same dose. These results suggest that ClopNPT has favorable PK/pharmacodynamic properties that can potentially overcome the attenuated PK properties of clopidogrel and thus significantly improve the efficacy of antiplatelet therapy.
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Affiliation(s)
- Haoming Zhang
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
| | - D Adam Lauver
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
| | - Hui Wang
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
| | - Duxin Sun
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
| | - Paul F Hollenberg
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
| | - Y Eugene Chen
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
| | - Yoichi Osawa
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
| | - Daniel T Eitzman
- Departments of Pharmacology (H.Z., D.A.L., P.F.H., Y.O.) and Internal Medicine (H.W., Y.E.C., D.T.E.), University of Michigan Medical School, Ann Arbor, Michigan; and Department of Pharmaceutical Sciences (D.S.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan
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Kim SJ, Yoshikado T, Ieiri I, Maeda K, Kimura M, Irie S, Kusuhara H, Sugiyama Y. Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information. Drug Metab Dispos 2016; 44:1622-32. [PMID: 27457785 DOI: 10.1124/dmd.116.070276] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 07/22/2016] [Indexed: 11/22/2022] Open
Abstract
Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrel-mediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model. Clopidogrel increased the AUC of pioglitazone (2.0-fold) and repaglinide (3.1-fold) but did not significantly change the AUC of pitavastatin (1.1-fold). In addition, the AUC of pioglitazone M4, a CYP2C8-mediated metabolite of pioglitazone, was reduced to 70% of the control by coadministration of clopidogrel. The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-β-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1). In conclusion, a single 300 mg of clopidogrel mainly inhibits CYP2C8-mediated metabolism by clopidogrel acyl-β-glucuronide, but its effect on the pharmacokinetics of OATP1B1 substrates is negligible. Clopidogrel is expected to have an effect not only on CYP2C8 substrates, but also dual CYP2C8/OATP1B1 substrates as seen in the case of repaglinide.
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Affiliation(s)
- Soo-Jin Kim
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
| | - Takashi Yoshikado
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
| | - Ichiro Ieiri
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
| | - Kazuya Maeda
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
| | - Miyuki Kimura
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
| | - Shin Irie
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
| | - Hiroyuki Kusuhara
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
| | - Yuichi Sugiyama
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN, Yokohama, Japan (S. K., T.Y., Y.S.); Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugioka Memorial Hospital, Fukuoka, Japan (M.K., S.I.)
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Bohnert T, Patel A, Templeton I, Chen Y, Lu C, Lai G, Leung L, Tse S, Einolf HJ, Wang YH, Sinz M, Stearns R, Walsky R, Geng W, Sudsakorn S, Moore D, He L, Wahlstrom J, Keirns J, Narayanan R, Lang D, Yang X. Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions-an Industry Perspective. Drug Metab Dispos 2016; 44:1399-423. [PMID: 27052879 DOI: 10.1124/dmd.115.069096] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 03/31/2016] [Indexed: 12/15/2022] Open
Abstract
Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.
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Affiliation(s)
- Tonika Bohnert
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Aarti Patel
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Ian Templeton
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Yuan Chen
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Chuang Lu
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - George Lai
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Louis Leung
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Susanna Tse
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Heidi J Einolf
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Ying-Hong Wang
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Michael Sinz
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Ralph Stearns
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Robert Walsky
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Wanping Geng
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Sirimas Sudsakorn
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - David Moore
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Ling He
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Jan Wahlstrom
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Jim Keirns
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Rangaraj Narayanan
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Dieter Lang
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
| | - Xiaoqing Yang
- Biogen, Cambridge, Massachusetts (T.B.); GlaxoSmithKline R&D, Hertfordshire, United Kingdom (A.P.); Janssen R&D, Spring House, Pennsylvania (I.T.); Genentech, South San Francisco, California (Y.C.); Takeda, Cambridge, Massachusetts (C.L.); Eisai Inc., Andover, Massachusetts (G.L.); Pfizer Inc., Groton, Connecticut (L.L., S.T.); Novartis, East Hanover, New Jersey (H.J.E.); Merck & Co., Inc., Kenilworth, New Jersey (Y.-H.W.); Bristol Myers Squibb, Wallingford, Connecticut (M.S.); Vertex Pharmaceuticals Inc., Boston, Massachusetts (R.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.W., W.G.); Sanofi, Waltham, Massachusetts (S.S.); Roche Innovation Center, New York, New York (D.M.); Daiichi Sankyo, Edison, New Jersey (L.H.); Amgen Inc., Thousand Oaks, California (J.W.); Astellas, Northbrook, Illinois (J.K.); Celgene Corporation, Summit, New Jersey (R.N.); Bayer Pharma AG, Wuppertal, Germany (D.L.); and Incyte Corporation, Wilmington, Delaware (X.Y.)
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Shi J, Wang X, Eyler RF, Liang Y, Liu L, Mueller BA, Zhu HJ. Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms. Basic Clin Pharmacol Toxicol 2016; 119:555-561. [PMID: 27228223 DOI: 10.1111/bcpt.12625] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/13/2016] [Indexed: 12/22/2022]
Abstract
Oseltamivir, an inactive anti-influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non-genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1-mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the -816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (p = 0.039), while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (p = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, -816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, p = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations.
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Affiliation(s)
- Jian Shi
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Xinwen Wang
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Rachel F Eyler
- School of Pharmacy, University of Connecticut, Storrs, CT, USA
| | - Yan Liang
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.,The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Li Liu
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.,The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
| | - Bruce A Mueller
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Hao-Jie Zhu
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA
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Xu X, Zhao X, Yang Z, Wang H, Meng X, Su C, Liu M, Fawcett JP, Yang Y, Gu J. Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration. Molecules 2016; 21:molecules21060704. [PMID: 27248988 PMCID: PMC6274316 DOI: 10.3390/molecules21060704] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/19/2016] [Accepted: 05/25/2016] [Indexed: 01/07/2023] Open
Abstract
In the search for prodrug analogs of clopidogrel with improved metabolic characteristics and antiplatelet bioactivity, a group of clopidogrel and vicagrel analogs selectively deuterated at the benzylic methyl ester group were synthesized, characterized, and evaluated. The compounds included clopidogrel-d3 (8), 2-oxoclopidogrel-d3 (9), vicagrel-d3 (10a), and 12 vicagrel-d3 analogs (10b–10m) with different alkyl groups in the thiophene ester moiety. The D3C-O bond length in 10a was shown by X-ray single crystal diffraction to be shorter than the H3C-O bond length in clopidogrel, consistent with the slower rate of hydrolysis of 8 than of clopidogrel in rat whole blood in vitro. A study of the ability of the compounds to inhibit ADP-induced platelet aggregation in fresh rat whole blood collected 2 h after oral dosing of rats with the compounds (7.8 μmol/kg) showed that deuteration increased the activity of clopidogrel and that increasing the size of the alkyl group in the thiophene ester moiety reduced activity. A preliminary pharmacokinetic study comparing 10a with vicagrel administered simultaneously as single oral doses (72 μmol/kg of each drug) to male Wistar rats showed 10a generated more of its active metabolite than vicagrel. These results suggest that 10a is a potentially superior antiplatelet agent with improved metabolic characteristics and bioactivity, and less dose-related toxicity.
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Affiliation(s)
- Xueyu Xu
- College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China.
| | - Xue Zhao
- College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China.
| | - Zhichao Yang
- College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China.
| | - Hao Wang
- College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China.
| | - Xiangjun Meng
- Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China.
| | - Chong Su
- Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China.
| | - Mingyuan Liu
- Department of Pharmacology, School of Basic Medical Sciences, Jiamusi University, Jiamusi 154007, China.
| | - John Paul Fawcett
- School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand.
| | - Yan Yang
- Research Center for Drug Metabolism, Jilin University, Qianjin Street, Changchun 130012, China.
| | - Jingkai Gu
- College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, China.
- Clinical Pharmacology Center, Research Institute of Translational Medicine, The First Hospital of Jilin University, Dongminzhu Street, Changchun 130061, China.
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Laine M, Paganelli F, Bonello L. P2Y12-ADP receptor antagonists: Days of future and past. World J Cardiol 2016; 8:327-332. [PMID: 27231519 PMCID: PMC4877361 DOI: 10.4330/wjc.v8.i5.327] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 08/03/2015] [Accepted: 01/22/2016] [Indexed: 02/06/2023] Open
Abstract
Antiplatelet therapy is the cornerstone of the therapeutic arsenal in coronary artery disease. Thanks to a better understanding in physiology, pharmacology and pharmacogenomics huge progress were made in the field of platelet reactivity inhibition thus allowing the expansion of percutaneous coronary intervention. Stent implantation requires the combination of two antiplatelet agents acting in a synergistic way. Asprin inhibit the cyclo-oxygenase pathway of platelet activation while clopidogrel is a P2Y12 adenosine diphosphate (ADP)-receptor antagonist. This dual antiplatelet therapy has dramatically improved the prognosis of stented patients. However, due to pharmacological limitations of clopidogrel (interindividual variability in its biological efficacy, slow onset of action, mild platelet reactivity inhibition) ischemic recurrences remained high following stent implantation especially in acute coronary syndrome patients. Thus, more potent P2Y12-ADP receptor inhibitors were developped including prasugrel, ticagrelor and more recently cangrelor to overcome these pitfalls. These new agents reduced the rate of thrombotic events in acute coronary syndrome patients at the cost of an increased bleeding risk. The abundance in antiplatelet agents allow us to tailor our strategy based on the thrombotic/bleeding profile of each patient. Recently, the ACCOAST trial cast a doubt on the benefit of pre treatment in non-ST segment elevation acute coronary syndrome. The aim of the present review is to summarize the results of the main studies dealing with antiplatelet therapy in stented/acute coronary syndromes patients.
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Shi J, Wang X, Nguyen J, Wu AH, Bleske BE, Zhu HJ. Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation. Drug Metab Dispos 2016; 44:554-9. [PMID: 26817948 PMCID: PMC4810765 DOI: 10.1124/dmd.115.068536] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 01/20/2016] [Indexed: 12/11/2022] Open
Abstract
Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wild-type CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy.
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Affiliation(s)
- Jian Shi
- Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Xinwen Wang
- Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Jenny Nguyen
- Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Audrey H Wu
- Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Barry E Bleske
- Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
| | - Hao-Jie Zhu
- Department of Clinical Pharmacy (J.S., X.W., H.-J.Z.), and Department of Pharmaceutical Sciences (J.N.), University of Michigan, Ann Arbor, Michigan; Cardiovascular Center, University of Michigan Health Systems, Ann Arbor, Michigan (A.H.W.); and Department of Pharmacy Practice and Administrative Sciences, University of New Mexico, Albuquerque, New Mexico (B.E.B.)
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Kurokawa T, Fukami T, Yoshida T, Nakajima M. Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog. Drug Metab Dispos 2016; 44:409-16. [PMID: 26718653 DOI: 10.1124/dmd.115.068221] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 12/29/2015] [Indexed: 02/13/2025] Open
Abstract
Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CLint value of 50.0 ± 1.2 ml/min/mg protein with a similar Km value to human intestinal and liver microsomes, whereas the CLint values of human CES1 and CES2 were 4.6 ± 0.1 and 6.6 ± 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar Km values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.
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Affiliation(s)
- Takaya Kurokawa
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
| | - Tatsuki Fukami
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
| | - Tomohiro Yoshida
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
| | - Miki Nakajima
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan
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Kazui M, Ogura Y, Hagihara K, Kubota K, Kurihara A. Human Intestinal Raf Kinase Inhibitor Protein (RKIP) Catalyzes Prasugrel as a Bioactivation Hydrolase. Drug Metab Dispos 2016; 44:115-23. [PMID: 26558823 DOI: 10.1124/dmd.115.066290] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/04/2015] [Indexed: 02/13/2025] Open
Abstract
Prasugrel is a thienopyridine antiplatelet prodrug that undergoes rapid hydrolysis in vivo to a thiolactone metabolite by human carboxylesterase-2 (hCE2) during gastrointestinal absorption. The thiolactone metabolite is further converted to a pharmacologically active metabolite by cytochrome P450 isoforms. The aim of the current study was to elucidate hydrolases other than hCE2 involved in the bioactivation step of prasugrel in human intestine. Using size-exclusion column chromatography of a human small intestinal S9 fraction, another peak besides the hCE2 peak was observed to have prasugrel hydrolyzing activity, and this protein was found to have a molecular weight of about 20 kDa. This prasugrel hydrolyzing protein was successfully purified from a monkey small intestinal cytosolic fraction by successive four-step column chromatography and identified as Raf-1 kinase inhibitor protein (RKIP) by liquid chromatography-tandem mass spectrometry. Second, we evaluated the enzymatic kinetic parameters for prasugrel hydrolysis using recombinant human RKIP and hCE2 and estimated the contributions of these two hydrolyzing enzymes to the prasugrel hydrolysis reaction in human intestine, which were approximately 40% for hRKIP and 60% for hCE2. Moreover, prasugrel hydrolysis was inhibited by anti-hRKIP antibody and carboxylesterase-specific chemical inhibitor (bis p-nitrophenyl phosphate) by 30% and 60%, respectively. In conclusion, another protein capable of hydrolyzing prasugrel to its thiolactone metabolite was identified as RKIP, and this protein may play a significant role with hCE2 in prasugrel bioactivation in human intestine. RKIP is known to have diverse functions in many intracellular signaling cascades, but this is the first report describing RKIP as a hydrolase involved in drug metabolism.
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Affiliation(s)
- Miho Kazui
- Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), Tokyo, Japan
| | - Yuji Ogura
- Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), Tokyo, Japan
| | - Katsunobu Hagihara
- Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), Tokyo, Japan
| | - Kazuishi Kubota
- Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), Tokyo, Japan
| | - Atsushi Kurihara
- Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. (M.K., K.H., A.K.), and Daiichi Sankyo RD Novare Co., Ltd. (Y.O., K.K.), Tokyo, Japan
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44
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Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases. Eur J Pharm Sci 2015; 78:47-53. [PMID: 26164127 DOI: 10.1016/j.ejps.2015.07.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Revised: 06/28/2015] [Accepted: 07/07/2015] [Indexed: 11/23/2022]
Abstract
Human arylacetamide deacetylase (AADAC) is an esterase responsible for the hydrolysis of some drugs, including flutamide, indiplon, phenacetin, and rifamycins. AADAC is highly expressed in the human liver, where carboxylesterase (CES) enzymes, namely, CES1 and CES2, are also expressed. It is generally recognized that CES1 prefers compounds with a large acyl moiety and a small alcohol or amine moiety as substrates, whereas CES2 prefers compounds with a small acyl moiety and a large alcohol or amine moiety. In a comparison of the chemical structures of known AADAC substrates, AADAC most likely prefers compounds with the same characteristics as does CES2. However, the substrate specificity of human AADAC has not been fully clarified. To expand the knowledge of substrates of human AADAC, we measured its hydrolase activities toward 13 compounds, including known human CES1 and CES2 substrates, using recombinant enzymes expressed in Sf21 cells. Recombinant AADAC catalyzed the hydrolysis of fluorescein diacetate, N-monoacetyldapsone, and propanil, which possess notably small acyl moieties, and these substrates were also hydrolyzed by CES2. However, AADAC could not hydrolyze another CES2 substrate, procaine, which possesses a moderately small acyl moiety. In addition, AADAC did not hydrolyze several known CES1 substrates, including clopidogrel and oseltamivir, which have large acyl moieties and small alcohol moieties. Collectively, these results suggest that AADAC prefers compounds with smaller acyl moieties than does CES2. The role of AADAC in the hydrolysis of drugs has been clarified. For this reason, AADAC should receive attention in ADMET studies during drug development.
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Shaw SA, Balasubramanian B, Bonacorsi S, Cortes JC, Cao K, Chen BC, Dai J, Decicco C, Goswami A, Guo Z, Hanson R, Humphreys WG, Lam PYS, Li W, Mathur A, Maxwell BD, Michaudel Q, Peng L, Pudzianowski A, Qiu F, Su S, Sun D, Tymiak AA, Vokits BP, Wang B, Wexler R, Wu DR, Zhang Y, Zhao R, Baran PS. Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development. J Org Chem 2015; 80:7019-32. [PMID: 26151079 DOI: 10.1021/acs.joc.5b00632] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.
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Affiliation(s)
- Scott A Shaw
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Balu Balasubramanian
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Samuel Bonacorsi
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Janet Caceres Cortes
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Kevin Cao
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Bang-Chi Chen
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Jun Dai
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Carl Decicco
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Animesh Goswami
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Zhiwei Guo
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Ronald Hanson
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - W Griffith Humphreys
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Patrick Y S Lam
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Wenying Li
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Arvind Mathur
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Brad D Maxwell
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Quentin Michaudel
- ‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Li Peng
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Andrew Pudzianowski
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Feng Qiu
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Shun Su
- ‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Dawn Sun
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Adrienne A Tymiak
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Benjamin P Vokits
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Bei Wang
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Ruth Wexler
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Dauh-Rurng Wu
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Yingru Zhang
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Rulin Zhao
- †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Phil S Baran
- ‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
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Cressman AM, Macdonald EM, Fernandes KA, Gomes T, Paterson JM, Mamdani MM, Juurlink DN. A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors. Br J Clin Pharmacol 2015; 80:662-9. [PMID: 25980448 PMCID: PMC4594702 DOI: 10.1111/bcp.12682] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 05/08/2015] [Accepted: 05/11/2015] [Indexed: 11/29/2022] Open
Abstract
Aims Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. Methods We conducted a nested case–control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor. Results Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings. Conclusions Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.
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Affiliation(s)
- Alex M Cressman
- The Institute for Clinical Evaluative Sciences, Toronto, Ontario.,Department of Medicine, Faculty of Medicine, University of Toronto, Ontario
| | - Erin M Macdonald
- The Institute for Clinical Evaluative Sciences, Toronto, Ontario
| | | | - Tara Gomes
- The Institute for Clinical Evaluative Sciences, Toronto, Ontario.,Institute of Health Policy, Management and Evaluation, Toronto, Ontario.,The Leslie Dan Faculty of Pharmacy, Toronto, Ontario.,Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's, Toronto, Ontario
| | - J Michael Paterson
- The Institute for Clinical Evaluative Sciences, Toronto, Ontario.,Institute of Health Policy, Management and Evaluation, Toronto, Ontario
| | - Muhammad M Mamdani
- The Institute for Clinical Evaluative Sciences, Toronto, Ontario.,Institute of Health Policy, Management and Evaluation, Toronto, Ontario.,The Leslie Dan Faculty of Pharmacy, Toronto, Ontario.,Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's, Toronto, Ontario.,Dalla Lana School of Public Health, University of Toronto, Ontario.,Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
| | - David N Juurlink
- The Institute for Clinical Evaluative Sciences, Toronto, Ontario.,Department of Medicine, Faculty of Medicine, University of Toronto, Ontario.,Institute of Health Policy, Management and Evaluation, Toronto, Ontario.,Sunnybrook Research Institute, Toronto, Ontario.,Department of Pediatrics, University of Toronto, Ontario, Canada
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47
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Simon N, Finzi J, Cayla G, Montalescot G, Collet JP, Hulot JS. Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients. Eur J Clin Pharmacol 2015; 71:1059-66. [PMID: 26071277 DOI: 10.1007/s00228-015-1882-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 06/02/2015] [Indexed: 12/15/2022]
Abstract
PURPOSE Proton-pump Inhibitors use and CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses and increased cardiovascular events. METHODS Post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 41) or homozygous (*2/*2, n = 7) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel loading dose. A PK/PD model was defined using the variation of the P2Y12 reaction unit relative to baseline. RESULTS Carriage of CYP2C19*2 allele and the use of omeprazole/esomeprazole were associated with the inter-individual variability in the active metabolite clearance. The relationship between inhibition of platelet aggregation (IPA, %) and the active metabolite AUC (h*μg/L) was described by a sigmoid function (Emax 56 ± 5%; EAUC50 15.9 ± 0.8 h*μg/L) with a gamma exponent (7.04 ± 2.26). CONCLUSION This on/off shape explains that a small variation of exposure may have a clinical relevance.
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Affiliation(s)
- Nicolas Simon
- Aix-Marseille Université, INSERM, UMR912 (SESSTIM), 13003, Marseille, France,
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48
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Tarkiainen EK, Holmberg MT, Tornio A, Neuvonen M, Neuvonen PJ, Backman JT, Niemi M. Carboxylesterase 1 c.428G>A single nucleotide variation increases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans. Clin Pharmacol Ther 2015; 97:650-8. [DOI: 10.1002/cpt.101] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 02/15/2015] [Indexed: 01/03/2023]
Affiliation(s)
- EK Tarkiainen
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB, Helsinki University Hospital; Helsinki Finland
| | - MT Holmberg
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB, Helsinki University Hospital; Helsinki Finland
| | - A Tornio
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB, Helsinki University Hospital; Helsinki Finland
| | - M Neuvonen
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB, Helsinki University Hospital; Helsinki Finland
| | - PJ Neuvonen
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB, Helsinki University Hospital; Helsinki Finland
| | - JT Backman
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB, Helsinki University Hospital; Helsinki Finland
| | - M Niemi
- Department of Clinical Pharmacology; University of Helsinki and HUSLAB, Helsinki University Hospital; Helsinki Finland
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49
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Rasmussen HB, Bjerre D, Linnet K, Jürgens G, Dalhoff K, Stefansson H, Hankemeier T, Kaddurah-Daouk R, Taboureau O, Brunak S, Houmann T, Jeppesen P, Pagsberg AK, Plessen K, Dyrborg J, Hansen PR, Hansen PE, Hughes T, Werge T. Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics. Pharmacogenomics 2015; 16:649-65. [PMID: 25896426 DOI: 10.2217/pgs.15.7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
CES1 is involved in the hydrolysis of ester group-containing xenobiotic and endobiotic compounds including several essential and commonly used drugs. The individual variation in the efficacy and tolerability of many drugs metabolized by CES1 is considerable. Hence, there is a large interest in individualizing the treatment with these drugs. The present review addresses the issue of individualized treatment with drugs metabolized by CES1. It describes the composition of the gene encoding CES1, reports variants of this gene with focus upon those with a potential effect on drug metabolism and provides an overview of the protein structure of this enzyme bringing notice to mechanisms involved in the regulation of enzyme activity. Subsequently, the review highlights drugs metabolized by CES1 and argues that individual differences in the pharmacokinetics of these drugs play an important role in determining drug response and tolerability suggesting prospects for individualized drug therapies. Our review also discusses endogenous substrates of CES1 and assesses the potential of using metabolomic profiling of blood to identify proxies for the hepatic activity of CES1 that predict the rate of drug metabolism. Finally, the combination of genetics and metabolomics to obtain an accurate prediction of the individual response to CES1-dependent drugs is discussed.
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Affiliation(s)
- Henrik Berg Rasmussen
- Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, 2 Boserupvej, DK-4000 Roskilde, Denmark
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50
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Polasek TM. Beyond CYP2C19 – A New Chapter in Clopidogrel Pharmacogenomics. JOURNAL OF PHARMACY PRACTICE AND RESEARCH 2015. [DOI: 10.1002/j.2055-2335.2011.tb00054.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Thomas M Polasek
- Department of Clinical PharmacologyFlinders University and Flinders Medical Centre Adelaide SA 5042
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