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Chiodi D, Ishihara Y. Tertiary Alcohol: Reaping the Benefits but Minimizing the Drawbacks of Hydroxy Groups in Drug Discovery. J Med Chem 2025; 68:7889-7913. [PMID: 40231785 DOI: 10.1021/acs.jmedchem.4c03078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025]
Abstract
Among the smaller substituents in the medicinal chemist's toolbox, the hydroxy (OH) group can bestow one of the largest impacts in the drug-like properties of a molecule. A previous study showed that an H-to-OH structural modification effectively decreases lipophilicity, increases solubility, and decreases hERG inhibition. Despite these benefits, an OH group is not always recommended in drug molecules because it presents a metabolic "soft spot" for oxidation and glucuronidation in primary and secondary alcohols. Furthermore, the OH group presents challenges in permeability. In contrast, tertiary alcohols (3° ROH) often display an improved metabolic profile because oxidation at the 3° ROH is not possible, and the geminal alkyl groups could sterically shield the OH group from glucuronidation and permeability challenges. Through a series of matched molecular pairs, this Perspective highlights the 3° ROH as a motif that can reap the benefits but minimize the drawbacks of hydroxy groups in drug discovery.
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Affiliation(s)
- Debora Chiodi
- Department of Chemistry, Takeda Pharmaceuticals, 9625 Towne Centre Drive, San Diego, California 92121, United States
| | - Yoshihiro Ishihara
- Department of Chemistry, Genesis Therapeutics, 11568 Sorrento Valley Road Suite 8, San Diego, California 92121, United States
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Tian M, Ye L, Liang B, Chen Y, Mei J, Zhao Z, Guo X, Xu M, Zhang J, Yang S. Pharmacokinetics and Bioequivalence of 2 Oral Formulations of Vildagliptin in Healthy Chinese Subjects. Clin Pharmacol Drug Dev 2025; 14:154-160. [PMID: 39444294 DOI: 10.1002/cpdd.1482] [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: 09/11/2024] [Accepted: 10/07/2024] [Indexed: 10/25/2024]
Abstract
A randomized, open-label, 2-period, 2-sequence crossover study was conducted to evaluate the pharmacokinetics and bioequivalence of 2 oral formulations of vildagliptin tablets under both fasting and fed conditions in healthy Chinese subjects. A total of 56 healthy subjects were randomized to receive a single 50-mg dose of either a generic vildagliptin tablet (T) or the reference formulation (R). The washout period was 3 days. Blood samples were collected up to 24 hours postdosing during each period and analyzed for vildagliptin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration-time curve from time 0 to the last measurable concentration, and area under the serum concentration-time curve from time 0 to infinity were all within the predefined bioequivalence range of 80%-125%. This indicates that the generic and reference formulations are bioequivalent under both fasting and fed states. All adverse events reported were mild and transient. High-fat meals delayed absorption and reduced the maximum peak concentration of both formulations; however, they did not affect the overall exposure. Therefore, vildagliptin can be taken without regard to meals.
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Affiliation(s)
- Mengli Tian
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Libing Ye
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Binhong Liang
- Zhejiang Huahai Pharmaceutical Co., Ltd., Linhai, Zhejiang, China
| | - Yingrong Chen
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Jue Mei
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Zhouming Zhao
- Zhejiang Huahai Pharmaceutical Co., Ltd., Linhai, Zhejiang, China
| | - Xiaodi Guo
- Zhejiang Huahai Pharmaceutical Co., Ltd., Linhai, Zhejiang, China
| | - Min Xu
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Jingyao Zhang
- Chengdu Finelyse Pharmaceutical Technology Co., Ltd., Sichuan, China
| | - Shuixin Yang
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
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Pasha M, Zamir A, Rasool MF, Saeed H, Ahmad T, Alqahtani NS, Alqahtani LS, Alqahtani F. A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment. Pharmaceuticals (Basel) 2024; 17:924. [PMID: 39065773 PMCID: PMC11280059 DOI: 10.3390/ph17070924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/24/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration-time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.
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Affiliation(s)
- Mahnoor Pasha
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (M.P.); (A.Z.)
| | - Ammara Zamir
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (M.P.); (A.Z.)
| | - Muhammad Fawad Rasool
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (M.P.); (A.Z.)
| | - Hamid Saeed
- Section of Pharmaceutics, University College of Pharmacy, Allama Iqbal Campus, University of the Punjab, Lahore 54000, Pakistan;
| | - Tanveer Ahmad
- Institute for Advanced Biosciences (IAB), CNRS UMR5309, INSERM U1209, Grenoble Alpes University, 38700 La Tronche, France;
| | - Nawaf Shalih Alqahtani
- King Abdulaziz Medical City, Riyadh Region Ministry of National Guard, Health Affairs, Riyadh 11426, Saudi Arabia;
| | - Lamya Saif Alqahtani
- Department of Cardiology, Prince Sultan Cardiac Center, Riyadh 11625, Saudi Arabia;
| | - Faleh Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Yoo H, Shin W, Lee B, Park J, Lee Y, Kim A. Pharmacokinetics and Food Effect Between a 100-mg Sustained-Release Tablet and a 50-mg Immediate-Release Tablet of Vildagliptin in Healthy Subjects. Clin Pharmacol Drug Dev 2024; 13:122-127. [PMID: 37548105 DOI: 10.1002/cpdd.1313] [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: 06/20/2023] [Accepted: 07/19/2023] [Indexed: 08/08/2023]
Abstract
Vildagliptin is one of the dipeptidyl peptidase-4 inhibitors. This study aimed to compare vildagliptin exposure between 50-mg immediate-release (IR) and 100-mg new sustained-release (SR) tablets, and evaluate the food effect on the pharmacokinetics (PKs) of vildagliptin. A randomized, open-label, 3-period, 3-treatment, 6-sequence crossover study was conducted on healthy subjects. During each period, subjects received the SR tablet either in the fasted (T1) or high-fat fed (T2) state once a day, or IR tablets administered twice a day in the fasted state (R). Blood samples for PK analysis were obtained serially up to 24 hours after dosing. Thirty-four subjects completed the study. The geometric mean ratios for the Cmax and AUC0-24h of T1 to R were 1.15 and 0.89, respectively. The corresponding values of T2 to T1 were 0.94 and 1.07, respectively. Vildagliptin exposure over 24 hours was similar between the SR and IR tablets. In addition, the PK profiles of the SR tablets were not altered by food. The SR tablets can be administered without a food effect and be an alternative option to IR tablets.
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Affiliation(s)
- Hyounggyoon Yoo
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Wonsuk Shin
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - BackHwan Lee
- Department of Clinical Development, Alvogen Korea, Yeongdeungpo-gu, Seoul, Republic of Korea
| | - JinSoo Park
- Department of Clinical Development, Alvogen Korea, Yeongdeungpo-gu, Seoul, Republic of Korea
| | - Yilseob Lee
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Anhye Kim
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
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Kim KY, Jeong YJ, Park SY, Park EJ, Jeon JH, Song IS, Liu KH. Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats. Pharmaceutics 2024; 16:106. [PMID: 38258116 PMCID: PMC10819019 DOI: 10.3390/pharmaceutics16010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin-cysteine adduct was also found in saxagliptin-administered male Sprague-Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury.
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Affiliation(s)
- Ki-Young Kim
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Yeo-Jin Jeong
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - So-Young Park
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
- Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Eun-Ji Park
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Ji-Hyeon Jeon
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Im-Sook Song
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Kwang-Hyeon Liu
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
- Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea
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Pasha M, Zamir A, Ashraf W, Imran I, Saeed H, Rehman AU, Aziz M, Alqahtani F, Rasool MF. A systematic review on the clinical pharmacokinetics of vildagliptin in healthy and disease populations. Expert Opin Drug Metab Toxicol 2023; 19:991-1003. [PMID: 38008954 DOI: 10.1080/17425255.2023.2288252] [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: 07/24/2023] [Accepted: 11/22/2023] [Indexed: 11/28/2023]
Abstract
INTRODUCTION Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug. METHODS The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies. RESULTS The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards. CONCLUSIONS This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.
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Affiliation(s)
- Mahnoor Pasha
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Ammara Zamir
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Waseem Ashraf
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Imran Imran
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Hamid Saeed
- Allama Iqbal Campus, University College of Pharmacy, Lahore, Pakistan
| | - Anees Ur Rehman
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Majid Aziz
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Faleh Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Muhammad Fawad Rasool
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
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Li HX, Sun MR, Zhang Y, Song LL, Zhang F, Song YQ, Hou XD, Ge GB. Human Carboxylesterase 1A Plays a Predominant Role in Hydrolysis of the Anti-Dyslipidemia Agent Fenofibrate in Humans. Drug Metab Dispos 2023; 51:1490-1498. [PMID: 37550069 DOI: 10.1124/dmd.123.001365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/09/2023] Open
Abstract
Fenofibrate, a marketed peroxisome proliferator-activated receptor-α (PPARα) agonist, has been widely used for treating severe hypertriglyceridemia and mixed dyslipidemia. As a canonical prodrug, fenofibrate can be rapidly hydrolyzed to release the active metabolite (fenofibric acid) in vivo, but the crucial enzyme(s) responsible for fenofibrate hydrolysis and the related hydrolytic kinetics have not been well-investigated. This study aimed to assign the key organs and crucial enzymes involved in fenofibrate hydrolysis in humans, as well as reveal the impact of fenofibrate hydrolysis on its non-PPAR-mediated biologic activities. Our results demonstrated that fenofibrate could be rapidly hydrolyzed in the preparations from both human liver and lung to release fenofibric acid. Reaction phenotyping assays coupling with chemical inhibition assays showed that human carboxylesterase 1A (hCES1A) played a predominant role in fenofibrate hydrolysis in human liver and lung, while human carboxylesterase 2A (hCES2A) and human monoacylglycerol esterase (hMAGL) contributed to a very lesser extent. Kinetic analyses showed that fenofibrate could be rapidly hydrolyzed by hCES1A in human liver preparations, while the inherent clearance of hCES1A-catalyzed fenofibrate hydrolysis is much higher (>200-fold) than than that of hCES2A or hMAGL. Biologic assays demonstrated that both fenofibrate and fenofibric acid showed very closed Nrf2 agonist effects, but fenofibrate hydrolysis strongly weakens its inhibitory effects against both hCES2A and hNtoum. Collectively, our findings reveal that the liver is the major organ and hCES1A is the predominant enzyme-catalyzing fenofibrate hydrolysis in humans, while fenofibrate hydrolysis significantly reduces inhibitory effects of fenofibrate against serine hydrolases. SIGNIFICANCE STATEMENT: Fenofibrate can be completely converted to fenofibric acid in humans and subsequently exert its pharmacological effects, but the hydrolytic pathways of fenofibrate in humans have not been well-investigated. This study reported that the liver was the predominant organ and human carboxylesterase 1A was the crucial enzyme involved in fenofibrate hydrolysis in humans.
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Affiliation(s)
- Hong-Xin Li
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
| | - Meng-Ru Sun
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
| | - Ya Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
| | - Li-Lin Song
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
| | - Feng Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
| | - Yun-Qing Song
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
| | - Xu-Dong Hou
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
| | - Guang-Bo Ge
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.-X.L., M.-R.S., Y.Z., L.-L.S., F.Z., Y.-Q.S., X.-D.H., G.-B.G.) and Liaoning Provincial Key Laboratory of Carbohydrates, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (L.-L.S.)
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Li Q, Deng X, Xu YJ, Dong L. Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants. J Med Chem 2023; 66:11593-11631. [PMID: 37647598 DOI: 10.1021/acs.jmedchem.3c00412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of long-acting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs.
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Affiliation(s)
- Qing Li
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Xiaoyan Deng
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Yan-Jun Xu
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Lin Dong
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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Foti RS. Cytochrome P450 and Other Drug-Metabolizing Enzymes As Therapeutic Targets. Drug Metab Dispos 2023; 51:936-949. [PMID: 37041085 DOI: 10.1124/dmd.122.001011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 03/12/2023] [Accepted: 03/27/2023] [Indexed: 04/13/2023] Open
Abstract
Cytochrome P450 and other families of drug-metabolizing enzymes are commonly thought of and studied for their ability to metabolize xenobiotics and other foreign entities as they are eliminated from the body. Equally as important, however, is the homeostatic role that many of these enzymes play in maintaining the proper levels of endogenous signaling molecules such as lipids, steroids, and eicosanoids as well as their ability to modulate protein-protein interactions involved in downstream signaling cascades. Throughout the years, many of these endogenous ligands or protein partners of drug-metabolizing enzymes have been associated with a wide range of disease states from cancer to various cardiovascular, neurologic, or inflammatory diseases, prompting an interest in whether modulation of drug-metabolizing enzyme activity could have a subsequent pharmacological impact or lessening of disease severity. Beyond direct regulation of endogenous pathways, drug-metabolizing enzymes have also been proactively targeted for their ability to activate prodrugs with subsequent pharmacological activity or enhance the efficacy of a coadministered drug by inhibiting the metabolism of that drug through a rationally designed drug-drug interaction (i.e., ritonavir and human immunodeficiency virus antiretroviral therapy). The focus of this minireview will be to highlight research aimed at characterizing cytochrome P450 and other drug-metabolizing enzymes as therapeutic targets. Examples of successfully marketed drugs as well as early research efforts will be discussed. Finally, emerging areas of research utilizing typical drug-metabolizing enzymes to impact clinical outcomes will be discussed. SIGNIFICANCE STATEMENT: Although generally thought of for their drug-metabolizing capabilities, enzymes such as the cytochromes P450, glutathione S-transferases, soluble epoxide hydrolases, and others play a significant role in regulating key endogenous pathways, making them potential drug targets. This minireview will cover various efforts over the years to modulate drug-metabolizing enzyme activity toward pharmacological outcomes.
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Affiliation(s)
- Robert S Foti
- ADME & Discovery Toxicology, Merck & Co., Inc., Boston, Massachusetts
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10
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Patel M, Riede J, Bednarczyk D, Poller B, Deshmukh SV. Simplifying the Extended Clearance Concept Classification System (EC3S) to Guide Clearance Prediction in Drug Discovery. Pharm Res 2023; 40:937-949. [PMID: 36859748 DOI: 10.1007/s11095-023-03482-4] [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: 10/18/2022] [Accepted: 02/10/2023] [Indexed: 03/03/2023]
Abstract
PURPOSE The Extended Clearance Concept Classification System was established as a development-stage tool to provide a framework for identifying fundamental mechanism(s) governing drug disposition in humans. In the present study, the applicability of the EC3S in drug discovery has been investigated. In its current format, the EC3S relies on low-throughput hepatocyte uptake data, which are not frequently generated in a discovery setting. METHODS A relationship between hepatocyte uptake clearance and MDCK permeability was first established along with intrinsic clearance from human liver microsomes. The performance of this approach was examined by categorizing 64 drugs into EC3S classes and comparing the predicted major elimination pathway(s) to that observed in humans. As an extension of the work, the ability of the simplified EC3S to predict human systemic clearance based on intrinsic clearance generated using in-vitro metabolic systems was evaluated. RESULTS The assessment enabled the use of MDCK permeability and unscaled unbound intrinsic clearance to generate cut-off criteria to categorize compounds into four EC3S classes: Class 12ab, 2cd, 34ab, and 34cd, with major elimination mechanism(s) assigned to each class. The predictivity analysis suggested that systemic clearance could generally be predicted within threefold for EC3S class 12ab and 34ab compounds. For classes 2cd and 34cd, systemic clearance was poorly predicted using in-vitro systems explored in this study. CONCLUSION Collectively, our simplified classification approach is expected to facilitate the identification of mechanism(s) involved in drug elimination, faster resolution of in-vitro to in-vivo disconnects, and better design of mechanistic pharmacokinetic studies in drug discovery.
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Affiliation(s)
- Mitesh Patel
- Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue 2A/242, Cambridge, MA, 02139, USA
| | - Julia Riede
- Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Dallas Bednarczyk
- Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue 2A/242, Cambridge, MA, 02139, USA
| | - Birk Poller
- Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Sujal V Deshmukh
- Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue 2A/242, Cambridge, MA, 02139, USA.
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11
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Corredor JD, Febres-Molina C, Jaña GA, Jiménez VA. Insight into the Role of Active Site Protonation States and Water Molecules in the Catalytic Inhibition of DPP4 by Vildagliptin. J Chem Inf Model 2023; 63:1338-1350. [PMID: 36757339 DOI: 10.1021/acs.jcim.2c01558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Vildagliptin (VIL) is an antidiabetic drug that inhibits dipeptidyl peptidase-4 (DPP4) through a covalent mechanism. The molecular bases for this inhibitory process have been addressed experimentally and computationally. Nevertheless, relevant issues remain unknown such as the roles of active site protonation states and conserved water molecules nearby the catalytic center. In this work, molecular dynamics simulations were applied to examine the structures of 12 noncovalent VIL-DPP4 complexes encompassing all possible protonation states of three noncatalytic residues (His126, Asp663, Asp709) that were inconclusively predicted by different computational tools. A catalytically competent complex structure was only achieved in the system with His126 in its ε-form and nonconventional neutral states for Asp663/Asp709. This complex suggested the involvement of one water molecule in the catalytic process of His740/Ser630 activation, which was confirmed by QM/MM simulations. Our findings support the suitability of a novel water-mediated mechanism in which His740/Ser630 activation occurs concertedly with the nucleophilic attack on VIL and the imidate protonation by Tyr547. Then, the restoration of His740/ Tyr547 protonation states occurs via a two-water hydrogen bonding network in a low-barrier process, thus describing the final step of the catalytic cycle for the first time. Additionally, two hydrolytic mechanisms were proposed based on the hydrogen bonding networks formed by water molecules and the catalytic residues along the inhibitory mechanism. These findings are valuable to unveil the molecular features of the covalent inhibition of DPP4 by VIL and support the future development of novel derivatives with improved structural or mechanistic profiles.
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Affiliation(s)
- Jeisson D Corredor
- Doctorado en Fisicoquímica Molecular, Facultad de Ciencias Exactas, Universidad Andres Bello, República 275, Santiago 8370146, Chile
| | - Camilo Febres-Molina
- Doctorado en Fisicoquímica Molecular, Facultad de Ciencias Exactas, Universidad Andres Bello, República 275, Santiago 8370146, Chile
| | - Gonzalo A Jaña
- Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Autopista Concepción-Talcahuano 7100, Talcahuano 4260000, Chile
| | - Verónica A Jiménez
- Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Autopista Concepción-Talcahuano 7100, Talcahuano 4260000, Chile
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12
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Xie Y, Zhou Q, He Q, Wang X, Wang J. Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition. Acta Pharm Sin B 2022. [DOI: 10.1016/j.apsb.2022.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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13
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Guo Z, Kong F, Xie N, Chen Z, Hu J, Chen X. Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite. Pharm Res 2022; 39:2147-2162. [PMID: 35790618 DOI: 10.1007/s11095-022-03324-9] [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: 03/01/2022] [Accepted: 06/24/2022] [Indexed: 12/01/2022]
Abstract
PURPOSE To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7. METHODS The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences. RESULTS After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 μM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type. CONCLUSIONS The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.
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Affiliation(s)
- Zitao Guo
- School of Environmental Chemistry and Engineering, Shanghai University, 99 Shangda Road BaoShan District, Shanghai, 200444, China.,Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Fandi Kong
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ningjie Xie
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhendong Chen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Jiafeng Hu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoyan Chen
- School of Environmental Chemistry and Engineering, Shanghai University, 99 Shangda Road BaoShan District, Shanghai, 200444, China. .,Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
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14
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Jones RS, Leung C, Chang JH, Brown S, Liu N, Yan Z, Kenny JR, Broccatelli F. Application of empirical scalars to enable early prediction of human hepatic clearance using IVIVE in drug discovery: an evaluation of 173 drugs. Drug Metab Dispos 2022; 50:DMD-AR-2021-000784. [PMID: 35636770 DOI: 10.1124/dmd.121.000784] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 04/20/2022] [Accepted: 05/12/2022] [Indexed: 11/22/2022] Open
Abstract
The utilization of in vitro data to predict drug pharmacokinetics (PK) in vivo has been a consistent practice in early drug discovery for decades. However, its success is hampered by mispredictions attributed to uncharacterized biological phenomena/experimental artifacts. Predicted drug clearance (CL) from experimental data (i.e. hepatocyte intrinsic clearance: CLint, fraction unbound in plasma: fu,p) is often systematically underpredicted using the well-stirred model (WSM). The objective of this study was to evaluate using empirical scalars in the WSM to correct for CL mispredictions. Drugs (N=28) were used to generate numerical scalars on CLint (α), and fu,p (β) to minimize the error (AAFE) for CL predictions. These scalars were validated using an additional dataset (N=28 drugs) and applied to a non-redundant AstraZeneca (AZ) dataset available in the literature (N=117 drugs) for a total of 173 compounds. CL predictions using the WSM were improved for most compounds using an α value of 3.66 (~64%<2-fold) compared to no scaling (~46%<2-fold). Similarly, using a β value of 0.55 or combination of α and β scalars (values of 1.74 and 0.66, respectively) resulted in a similar improvement in predictions (~64%<2-fold and ~65%<2-fold, respectively). For highly bound compounds (fu,p{less than or equal to}0.01), AAFE was substantially reduced across all scaling methods. Using the β scalar alone or a combination of α and β appeared optimal; and produce larger magnitude corrections for highly-bound compounds. Some drugs are still disproportionally mispredicted, however the improvements in prediction error and simplicity of applying these scalars suggests its utility for early-stage CL predictions. Significance Statement In early drug discovery, prediction of human clearance using in vitro experimental data plays an essential role in triaging compounds prior to in vivo studies. These predictions have been systematically underestimated. Here we introduce empirical scalars calibrated on the extent of plasma protein binding that appear to improve clearance prediction across multiple datasets. This approach can be used in early phases of drug discovery prior to the availability of pre-clinical data for early quantitative predictions of human clearance.
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Affiliation(s)
| | | | - Jae H Chang
- Preclinical Development Sciences, ORIC Pharmaceuticals, United States
| | | | | | | | - Jane R Kenny
- Drug Metabolism & Pharmacokinetics, Genentech Inc, United States
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15
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Madny MA, Deshpande P, Tumuluri V, Borde P, Sangana R. Physiologically Based Biopharmaceutics Model of Vildagliptin Modified Release (MR) Tablets to Predict In Vivo Performance and Establish Clinically Relevant Dissolution Specifications. AAPS PharmSciTech 2022; 23:108. [PMID: 35386066 DOI: 10.1208/s12249-022-02264-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/21/2022] [Indexed: 11/30/2022] Open
Abstract
The objective of the study was to predict pharmacokinetic (PK) and pharmacodynamic (PD) parameters of matrix-based modified release (MR) drug product of vildagliptin. Physiologically based biopharmaceutics modeling (PBBM) was developed using GastroPlus™ based on the available data including immediate-release (IR) drug product of vildagliptin. In vitro-in vivo correlation (IVIVC) was developed using mechanistic deconvolution to predict plasma concentration-time profile and PK parameters for a MR drug product planned for clinical use. Both methods, i.e., PBBM and IVIVC, were compared for the predicted PK parameters. Integration of DDDPlus™ and GastroPlus™ modeling was performed to explore clinically relevant dissolution specifications for vildagliptin MR tablets. The bioequivalence (BE) between batches with different dissolution specifications was evaluated using virtual clinical trials. The PD effect of dipeptidyl peptidase-IV (DPP-IV) inhibition was simulated utilizing PDPlus™ model in GastroPlus™. The results indicated that IVIVC best correlated the simulated PK parameters with those observed with the clinical study. The outcomes highlight the importance of integration of in vitro and in silico tools towards predictability of PK and PD parameters for a MR drug product. However, the post absorptive phase was found to be more dependent on the demographics of the healthy subjects.
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16
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Using Metabolite Data to Develop Patient Centric Specification for Amide Impurity in Vildagliptin Tablets. Sci Pharm 2021. [DOI: 10.3390/scipharm90010001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Many specified impurities in vildagliptin’s finished product have been disclosed in the literature that are above their qualification threshold. We used the impurity B (amide impurity) as a case example to explore whether existing literature can be leveraged to determine the safe level of impurity and thereby develop a patient-centric specification (PCS) for impurities. No-observed-adverse-effect level (NOAEL) was derived from rate metabolism information and converted to human equivalent dose (HED). The HED was estimated as 6.5 mg/day. The high qualification levels are supported by repeat dose toxicity studies performed in rats, mice and dogs. Maximum theoretical amount (MTA) was correlated with the maximum observed amount (MOA) to verify whether the exposure was due to impurity and/or metabolite. MOA/MTA was found ≥1 suggesting that metabolism contributed to the amount excreted in feces and therefore could be used to further justify a higher specification limit than the usual one of ≤0.5%. Quite often the drug metabolism and degradation pathways overlap, resulting in the formation of identical constituents. Therefore, metabolism data can be leveraged for deriving safe levels of degradation impurities and develop PCS for impurities.
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17
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Lu J, Bian Y, Zhang H, Tang D, Tian X, Zhou X, Xu Z, Xiong Y, Gu Z, Yu Z, Wang T, Ding J, Yu Q, Ding J. The Metabolism and Excretion of the Dipeptidyl Peptidase 4 Inhibitor [ 14C] Cetagliptin in Healthy Volunteers. Xenobiotica 2021; 52:38-45. [PMID: 34743655 DOI: 10.1080/00498254.2021.2002973] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
1. The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50μCi [14C] cetagliptin.2. The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and feces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.3. Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulfate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and feces at low levels, except that metabolite M640B was not detected in feces. All metabolites were observed with < 10% of parent compound systemic exposure after oral administration.
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Affiliation(s)
- Jinmiao Lu
- Xiangya School of Pharmaceutical Sciences, Central South University, Hunan, China.,CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Yicong Bian
- Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hua Zhang
- Department of Clinical Pharmacology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dong Tang
- CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Xusheng Tian
- CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Xinyi Zhou
- CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Zengyan Xu
- CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Yating Xiong
- Value Pharmaceutical Services Co., Ltd, Jiangsu, China
| | - Zheming Gu
- Value Pharmaceutical Services Co., Ltd, Jiangsu, China
| | - Zhenwen Yu
- Value Pharmaceutical Services Co., Ltd, Jiangsu, China
| | - Tong Wang
- CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Juping Ding
- CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Qiang Yu
- CGeneTech (Suzhou, China) Co., Ltd, Jiangsu, China
| | - Jinsong Ding
- Xiangya School of Pharmaceutical Sciences, Central South University, Hunan, China
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18
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Mostafa RE, Morsi AH, Asaad GF. Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury. Res Pharm Sci 2021; 16:547-558. [PMID: 34522201 PMCID: PMC8407158 DOI: 10.4103/1735-5362.323920] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 12/25/2020] [Accepted: 05/23/2021] [Indexed: 12/27/2022] Open
Abstract
Background and purpose: The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats. Experimental approach: Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/kg) and VIL (10 mg/kg) for 2 weeks. Findings/Results: DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity via alleviation of all the above-mentioned parameters when compared to DXR-control rats. Conclusion and implications: The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1β, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.
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Affiliation(s)
- Rasha Ezzat Mostafa
- Pharmacology Department, Medical Research Division, National Research Centre, Dokki, Cairo, Egypt
| | - Azza Hassan Morsi
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Gihan Farag Asaad
- Pharmacology Department, Medical Research Division, National Research Centre, Dokki, Cairo, Egypt
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19
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Zhang Q, Liu JL, Feng XX, Liu JC. Nitrile-containing copper(ii) porphyrin coordination complexes for efficient anticancer activity and mechanism research. NEW J CHEM 2021. [DOI: 10.1039/d1nj00326g] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Synthesis and anticancer activity of nitrile-containing copper(ii) porphyrin coordination complexes.
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Affiliation(s)
- Qian Zhang
- Key Laboratory of Eco-Functional Polymer Materials of the Ministry of Education
- Key Laboratory of Eco-Environmental Polymer Materials of Gansu Province
- Key Laboratory of Bioelectrochemistry & Environmental Analysis of Gansu Province
- College of Chemistry and Chemical Engineering
- Northwest Normal University
| | - Jin-Li Liu
- Key Laboratory of Eco-Functional Polymer Materials of the Ministry of Education
- Key Laboratory of Eco-Environmental Polymer Materials of Gansu Province
- Key Laboratory of Bioelectrochemistry & Environmental Analysis of Gansu Province
- College of Chemistry and Chemical Engineering
- Northwest Normal University
| | - Xiao-Xia Feng
- Key Laboratory of Eco-Functional Polymer Materials of the Ministry of Education
- Key Laboratory of Eco-Environmental Polymer Materials of Gansu Province
- Key Laboratory of Bioelectrochemistry & Environmental Analysis of Gansu Province
- College of Chemistry and Chemical Engineering
- Northwest Normal University
| | - Jia-Cheng Liu
- Key Laboratory of Eco-Functional Polymer Materials of the Ministry of Education
- Key Laboratory of Eco-Environmental Polymer Materials of Gansu Province
- Key Laboratory of Bioelectrochemistry & Environmental Analysis of Gansu Province
- College of Chemistry and Chemical Engineering
- Northwest Normal University
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20
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Zhang L, Jiang L, Guan X, Cai L, Wang J, Xiang P, Pan J, Hu X. A facile method to synthesize vildagliptin. JOURNAL OF CHEMICAL RESEARCH 2020. [DOI: 10.1177/1747519820967123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
An efficient and high-yielding synthetic method for the preparation of vildagliptin via four steps is reported. The process starts from L-proline and involves a successful reaction with chloroacetyl chloride in tetrahydrofuran to afford ( S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid, followed by a reaction with acetonitrile in the presence of sulfuric acid to give ( S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. This is then reacted with 3-aminoadamantanol to give vildagliptin. 3-Aminoadamantanol is prepared from 1-aminoadamantane hydrochloride via oxidation with sulfuric acid/nitric acid and boric acid as the catalyst followed by ethanol extraction. The overall yield is 95%.
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Affiliation(s)
- Li Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, P.R. China
| | - Lan Jiang
- College of Environment and Resources, Chongqing Technology and Business University, Chongqing, P.R. China
| | - Xiaoshu Guan
- Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, P.R. China
| | - Linhong Cai
- Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, P.R. China
| | - Jingyu Wang
- Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, P.R. China
| | - Peng Xiang
- Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, P.R. China
| | - Junyi Pan
- Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, P.R. China
| | - Xiangnan Hu
- Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, P.R. China
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21
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Mikov M, Pavlović N, Stanimirov B, Đanić M, Goločorbin-Kon S, Stankov K, Al-Salami H. DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment. Eur J Drug Metab Pharmacokinet 2020; 45:1-14. [PMID: 31385198 DOI: 10.1007/s13318-019-00570-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.
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Affiliation(s)
- Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia.
| | - Nebojša Pavlović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Bojan Stanimirov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Maja Đanić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Svetlana Goločorbin-Kon
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Karmen Stankov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Hani Al-Salami
- Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Biosciences Research Precinct, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
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22
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Khalil R, Shata A, Abd El-Kader EM, Sharaf H, Abdo WS, Amin NA, Saber S. Vildagliptin, a DPP-4 inhibitor, attenuates carbon tetrachloride-induced liver fibrosis by targeting ERK1/2, p38α, and NF-κB signaling. Toxicol Appl Pharmacol 2020; 407:115246. [PMID: 32956689 DOI: 10.1016/j.taap.2020.115246] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/12/2020] [Accepted: 09/16/2020] [Indexed: 02/08/2023]
Abstract
Mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-ĸB signaling have been recognized for their causal connection with liver fibrosis. Hence, it is encouraging to discover drugs that can modify the interactions between these signaling cascades. It has been suggested that glucagon-like peptide-1 receptors (GLP-1Rs) might have a role in the observed hepatoprotection of dipeptidyl peptidase-4 inhibitors other than vildagliptin (VLD). Consequently, we aimed to elucidate the mechanisms underlying its potential antifibrotic activity in a CCl4-intoxicated mouse model. VLD increased the percentage of viable CCl4-intoxicated primary rat hepatocytes in vitro. It also attenuated hepatic fibrosis, improved liver function, and prolonged survival of CCl4-intoxicated mice in a dose-dependent manner. This hepatoprotection might be mediated mainly through interference with extracellular signal-regulated protein kinase 1/2 phosphorylation, the most downstream signal of the MAPK pathway. In addition, VLD hepatoprotective activity could be partially mediated through inhibition of p38α phosphorylation and phosphorylation-induced NF-ĸB activation. As a result, VLD downregulated profibrogenic mediators, such as tumor necrosis factor α, transforming growth factor β, tissue inhibitor of metalloproteinase 1 and platelet-derived growth factor BB. Consequently, decreased expression levels of fibrosis markers, such as hydroxyproline and α smooth muscle actin, were confirmed. VLD showed a strong trend toward increasing the antioxidant defense machinery of fibrotic tissue, and we confirmed that GLP-1Rs were not implicated in the observed hepatoprotection. Since VLD poses little risk of hypoglycemia and is a safe drug for patients with liver injury, it may be a hopeful candidate for adjuvant treatment of liver fibrosis in humans.
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Affiliation(s)
- Rania Khalil
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Ahmed Shata
- Department of Clinical pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Eman M Abd El-Kader
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Hossam Sharaf
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Walied S Abdo
- Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Noha A Amin
- Department of Haematology, Theodor Bilharz Research Institute, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
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Sivaramakarthikeyan R, Iniyaval S, Saravanan V, Lim WM, Mai CW, Ramalingan C. Molecular Hybrids Integrated with Benzimidazole and Pyrazole Structural Motifs: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies. ACS OMEGA 2020; 5:10089-10098. [PMID: 32391496 PMCID: PMC7203960 DOI: 10.1021/acsomega.0c00630] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/13/2020] [Indexed: 02/08/2023]
Abstract
Synthesis of a series of benzimidazole-ornamented pyrazoles, 6a-6j has been obtained from arylhydrazine and aralkyl ketones via a multistep synthetic strategy. Among them, a hybrid-possessing para-nitrophenyl moiety connected to a pyrazole scaffold (6a) exerted the highest anti-inflammatory activity, which is superior to the standard, diclofenac sodium. While executing the 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity, a hybrid-possessing para-bromophenyl unit integrated at the pyrazole structural motif (6i) exhibited the highest activity among the hybrids examined. Besides, evaluation of anticancer potency of the synthesized hybrids revealed that the one containing a para-fluorophenyl unit tethered at the pyrazole nucleus (6h) showed the highest activity against both the pancreatic cancer cells (SW1990 and AsPCl) investigated. Considerable binding affinity between B-cell lymphoma and the hybrid, 6h has been reflected while performing molecular docking studies (-8.65 kcal/mol). The outcomes of the investigation expose that these hybrids could be used as effective intermediates to construct more potent biological agents.
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Affiliation(s)
- Ramar Sivaramakarthikeyan
- Department
of Chemistry, School of Advanced Sciences, Kalasalingam Academy of Research and Education (Deemed to be University), Krishnankoil 626 126, Tamilnadu, India
| | - Shunmugam Iniyaval
- Department
of Chemistry, School of Advanced Sciences, Kalasalingam Academy of Research and Education (Deemed to be University), Krishnankoil 626 126, Tamilnadu, India
| | - Vadivel Saravanan
- Department
of Chemistry, School of Advanced Sciences, Kalasalingam Academy of Research and Education (Deemed to be University), Krishnankoil 626 126, Tamilnadu, India
| | - Wei-Meng Lim
- School
of Pharmacy, International Medical University, 126 Jalan Jalil Perkasa 19, Bukit
Jalil, Kuala Lumpur 57000, Malaysia
| | - Chun-Wai Mai
- School
of Pharmacy, International Medical University, 126 Jalan Jalil Perkasa 19, Bukit
Jalil, Kuala Lumpur 57000, Malaysia
- Center
for Cancer and Stem Cell Research, Institute for Research, Development
and Innovation (IRDI), International Medical
University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Chennan Ramalingan
- Department
of Chemistry, School of Advanced Sciences, Kalasalingam Academy of Research and Education (Deemed to be University), Krishnankoil 626 126, Tamilnadu, India
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Gu N, Park SI, Chung H, Jin X, Lee S, Kim TE. Possibility of pharmacokinetic drug interaction between a DPP-4 inhibitor and a SGLT2 inhibitor. Transl Clin Pharmacol 2020; 28:17-33. [PMID: 32274378 PMCID: PMC7136081 DOI: 10.12793/tcp.2020.28.e4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/23/2022] Open
Abstract
Type 2 diabetes mellitus is a multifactorial condition characterized by high level of sugar in the blood. To control hyperglycemia, combination therapy is recommended if monotherapy fails to achieve glycemic control. The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose cotransporter type 2 (SGLT2) inhibitor is a promising option of the combination therapies in terms of safety as well as efficacy. Despite of the value of combination therapy of these two agents, the pharmacokinetic drug interactions between these two classes of agents have been evaluated in a few drugs. Thus, we reviewed the potential pharmacokinetic drug interaction based on the in vitro metabolism- and transporter-mediated drug interaction information as well as drug interaction studies in human, between a DPP-4 inhibitor and a SGLT2 inhibitor which are marketed in South Korea.
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Affiliation(s)
- Namyi Gu
- Department of Clinical Pharmacology and Therapeutics, Clinical Trial Center, Dongguk University College of Medicine and Ilsan Hospital, Goyang, Korea
| | - Sang-In Park
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Korea
| | - Hyewon Chung
- Department of Clinical Pharmacology and Toxicology, Korea University Guro Hospital, Seoul, Korea
| | - Xuanyou Jin
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - SeungHwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - Tae-Eun Kim
- Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, Korea
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Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis. Int J Mol Sci 2020; 21:ijms21072275. [PMID: 32218354 PMCID: PMC7177465 DOI: 10.3390/ijms21072275] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/19/2020] [Accepted: 03/23/2020] [Indexed: 12/13/2022] Open
Abstract
Vildagliptin is a representative of Dipeptidyl Peptidase-4 (DPP-4) inhibitors, antihyperglycemic drugs, approved for use as monotherapy and combination therapy in type 2 diabetes mellitus. By inhibiting enzymatic decomposition, DPP-4 inhibitors increase the half-life of incretins such as GLP-1 (Glucagon-like peptide-1) and GIP (Gastric inhibitors polypeptide) and prolong their action. Some studies present results suggesting the anti-sclerotic and vasculoprotective effects of vildagliptin reaching beyond glycemic control. Vildagliptin is able to limit inflammation by suppression of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway and proinflammatory agents such as TNF-α (tumor necrosis factor α), IL-1β (Interleukin-1β), and IL-8 (Interleukin 8). Moreover, vildagliptin regulates lipid metabolism; attenuates postprandial hypertriglyceridemia; and lowers serum triglycerides, apolipoprotein B, and blood total cholesterol levels. This DPP-4 inhibitor also reduces macrophage foam cell formation, which plays a key role in atheromatous plaque formation and stability. Vildagliptin reduces vascular stiffness via elevation of nitric oxide synthesis, improves vascular relaxation, and results in reduction in both systolic and diastolic blood pressure. Treatment with vildagliptin lowers the level of PAI-1 presenting possible antithrombotic effect. By affecting the endothelium, inflammation, and lipid metabolism, vildagliptin may affect the development of atherosclerosis at its various stages. The article presents a summary of the studies assessing vasculoprotective effects of vildagliptin with special emphasis on atherogenesis.
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Krishnan KG, Kumar CU, Lim WM, Mai CW, Thanikachalam PV, Ramalingan C. Novel cyanoacetamide integrated phenothiazines: Synthesis, characterization, computational studies and in vitro antioxidant and anticancer evaluations. J Mol Struct 2020; 1199:127037. [DOI: 10.1016/j.molstruc.2019.127037] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Surendran S, Sapkal R, Paul D, Nanjappan S. Effect of resveratrol on dipeptidyl peptidase-4 inhibitors pharmacokinetics: An in vitro and in vivo approach. Chem Biol Interact 2019; 315:108909. [PMID: 31786186 DOI: 10.1016/j.cbi.2019.108909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 11/06/2019] [Accepted: 11/25/2019] [Indexed: 12/26/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disorder with hyperglycemia being its hallmark symptom. The secondary symptom of DM is oxidative stress, which leads to the generation of free radicals. Diabetic nephropathy and neuropathy is the long-term effect of oxidative stress caused in DM, which leads to damage of kidneys and neurons respectively. Resveratrol (RES) is a phytochemical, found to be effective in the treatment of diabetic nephropathy and neuropathy. Due to its antioxidant property, it reduces the oxidative stress caused by DM. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 DM. In vitro and in vivo data depicted that the metabolism of alogliptin (ALO), saxagliptin (SAX) and sitagliptin (SIT) were decreased in presence of RES while metabolism of teneligliptin (TEN) was not affected in presence of RES. The results show that the alteration of the pharmacokinetics of ALO, SAX and SIT was due to inhibition of CYP P450 by RES. Thus, there was a significant pharmacokinetic interaction between RES-ALO, RES-SAX and RES-SIT. Hence, a dose reduction is required when RES therapy is taken in combination with ALO, SAX and SIT as there is an increase in drug exposure, which might lead to toxicity.
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Affiliation(s)
- Shruti Surendran
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Rekha Sapkal
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - David Paul
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Satheeshkumar Nanjappan
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
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Khojasteh SC, Bumpus NN, Driscoll JP, Miller GP, Mitra K, Rietjens IMCM, Zhang D. Biotransformation and bioactivation reactions - 2018 literature highlights. Drug Metab Rev 2019; 51:121-161. [PMID: 31170851 DOI: 10.1080/03602532.2019.1615937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In the past three decades, ADME sciences have become an integral component of the drug discovery and development process. At the same time, the field has continued to evolve, thus, requiring ADME scientists to be knowledgeable of and engage with diverse aspects of drug assessment: from pharmacology to toxicology, and from in silico modeling to in vitro models and finally in vivo models. Progress in this field requires deliberate exposure to different aspects of ADME; however, this task can seem daunting in the current age of mass information. We hope this review provides a focused and brief summary of a wide array of critical advances over the past year and explains the relevance of this research ( Table 1 ). We divided the articles into categories of (1) drug optimization, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation. This annual review is the fourth of its kind (Baillie et al. 2016 ; Khojasteh et al. 2017 , 2018 ). We have followed the same format we used in previous years in terms of the selection of articles and the authoring of each section. This effort in itself also continues to evolve. I am pleased that Rietjens, Miller, and Mitra have again contributed to this annual review. We would like to welcome Namandjé N. Bumpus, James P. Driscoll, and Donglu Zhang as authors for this year's issue. We strive to maintain a balance of authors from academic and industry settings. We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review. Cyrus Khojasteh, on behalf of the authors.
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Affiliation(s)
- S Cyrus Khojasteh
- Department of Drug Metabolism and Pharmacokinetics, Genentech Inc , South San Francisco , CA , USA
| | - Namandjé N Bumpus
- Department of Medicine - Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - James P Driscoll
- Department of Drug Metabolism and Pharmacokinetics, MyoKardia Inc. , South San Francisco , CA , USA
| | - Grover P Miller
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Kaushik Mitra
- Department of Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories (MRL), Merck & Co., Inc , West Point , PA , USA
| | | | - Donglu Zhang
- Department of Drug Metabolism and Pharmacokinetics, Genentech Inc , South San Francisco , CA , USA
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Mizuno K, Takeuchi K, Umehara K, Nakajima M. Identification of Novel Metabolites of Vildagliptin in Rats: Thiazoline-Containing Thiol Adducts Formed via Cysteine or Glutathione Conjugation. Drug Metab Dispos 2019; 47:809-817. [PMID: 31097424 DOI: 10.1124/dmd.119.086546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 05/14/2019] [Indexed: 01/18/2023] Open
Abstract
Vildagliptin (VG), a dipeptidyl peptidase-4 inhibitor, is used for treating type 2 diabetes. On rare occasions, VG causes liver injury as an adverse reaction. One case report suggested the involvement of immune responses in the hepatotoxicity, but the underlying mechanisms are unknown. We recently reported that VG binds covalently in vitro to l-cysteine to produce a thiazoline acid metabolite, M407, implying that the covalent binding may trigger the immune-mediated hepatotoxicity. There was no evidence, however, that such a thiazoline acid metabolite was formed in vivo. In the present study, we administered a single oral dose of VG to male Sprague-Dawley rats, and detected M407 in plasma. The sum of urinary and fecal excretions of M407 reached approximately 2% of the dose 48 hours postdosing. Using bile duct-cannulated rats, we demonstrated that M407 was secreted into bile as a glucuronide, designated as M583. Another newly identified thiazoline metabolite of VG, the cysteinylglycine conjugate M464, was detected in urine, feces, and bile. The formation of M464 was confirmed by in vitro incubation of VG with glutathione even in the absence of metabolic enzymes. A glutathione adduct against the nitrile moiety M611 was also detected in vitro but not in vivo. In summary, we found three new thiazoline-containing thiol adduct metabolites in VG-administered rats. Nonenzymatic covalent binding of VG would likely occur in humans, and it may be relevant to predicting adverse reactions.
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Affiliation(s)
- Katsuhiko Mizuno
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.M., K.T.); Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.U.); Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa Japan (K.M., M.N.); and WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Japan (M.N.)
| | - Kenji Takeuchi
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.M., K.T.); Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.U.); Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa Japan (K.M., M.N.); and WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Japan (M.N.)
| | - Ken Umehara
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.M., K.T.); Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.U.); Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa Japan (K.M., M.N.); and WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Japan (M.N.)
| | - Miki Nakajima
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.M., K.T.); Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan (K.U.); Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa Japan (K.M., M.N.); and WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Japan (M.N.)
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Makrilakis K. The Role of DPP-4 Inhibitors in the Treatment Algorithm of Type 2 Diabetes Mellitus: When to Select, What to Expect. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16152720. [PMID: 31366085 PMCID: PMC6696077 DOI: 10.3390/ijerph16152720] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/26/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus is a growing global public health problem, the prevalence of which is projected to increase in the succeeding decades. It is potentially associated with many complications, affecting multiple organs and causing a huge burden to the society. Due to its multi-factorial pathophysiology, its treatment is varied and based upon a multitude of pharmacologic agents aiming to tackle the many aspects of the disease pathophysiology (increasing insulin availability [either through direct insulin administration or through agents that promote insulin secretion], improving sensitivity to insulin, delaying the delivery and absorption of carbohydrates from the gastrointestinal tract, or increasing urinary glucose excretion). DPP-4 (dipeptidyl peptidase-4) inhibitors (or “gliptins”) represent a class of oral anti-hyperglycemic agents that inhibit the enzyme DPP-4, thus augmenting the biological activity of the “incretin” hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and restoring many of the pathophysiological problems of diabetes. They have already been used over more than a decade in the treatment of the disease. The current manuscript will review the mechanism of action, therapeutic utility, and the role of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Konstantinos Makrilakis
- National and Kapodistrian University of Athens Medical School, Laiko General Hospital, 17 Ag. Thoma St., 11527 Athens, Greece.
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Fredenhagen A, Kühnöl J, Kittelmann M, Oberer L. Gas-Phase Rearrangement of the O-Glucuronide of Vildagliptin Forms Product-Ion Fragments Suggesting Wrongly an N-Glucuronide. Drug Metab Dispos 2019; 47:189-193. [PMID: 30567879 DOI: 10.1124/dmd.118.085597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 12/17/2018] [Indexed: 11/22/2022] Open
Abstract
The O-glucuronide of vildagliptin, a dipeptidyl peptidase 4 inhibitor, is a major metabolite in monkeys and a minor metabolite in humans, rats, and dogs. Its product ion spectrum shows fragments that can be explained only by an N-glucuronide. Biotransformation using rat liver yielded milligram amounts of the O-glucuronide, and its structure was assigned unambiguously by nuclear magnetic resonance. The tandem mass spectra (MS/MS) of this compound was investigated in detail using MSn and accurate mass spectrometers and was identical to the animal metabolite. Thus, the MS/MS fragments suggesting an N-glucuronide had to be formed by gas-phase rearrangement. This gas-phase rearrangement can be observed on quadrupole time-of-flight and ion-trap mass instruments. The literature on gas-phase rearrangements is reviewed.
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Affiliation(s)
- Andreas Fredenhagen
- Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland
| | - Jürgen Kühnöl
- Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland
| | - Matthias Kittelmann
- Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland
| | - Lukas Oberer
- Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland
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Kong F, Pang X, Zhao J, Deng P, Zheng M, Zhong D, Chen X. Hydrolytic Metabolism of Cyanopyrrolidine DPP-4 Inhibitors Mediated by Dipeptidyl Peptidases. Drug Metab Dispos 2019; 47:238-248. [PMID: 30530814 DOI: 10.1124/dmd.118.084640] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/05/2018] [Indexed: 01/04/2023] Open
Abstract
Nitrile group biotransformation is an unusual or minor metabolic pathway for most nitrile-containing drugs. However, for some cyanopyrrolidine dipeptidyl peptidase 4 (DPP-4) inhibitors (vildagliptin, anagliptin, and besigliptin, but not saxagliptin), the conversion of nitrile group into carboxylic acid is their major metabolic pathway in vivo. DPP-4 was reported to be partly involved in the metabolism. In our pilot study, it was also observed that saxagliptin, a DPP-4 specific inhibitor, decreased the plasma exposures of besigliptin carboxylic acid in rats by only 20%. Therefore, it is speculated that some other enzymes may participate in nitrile group hydrolysis. After incubating gliptins with the cytosol, microsomes, and mitochondria of liver and kidney, carboxylic acid metabolites could all be formed. In recombinant DPP family such as DPP-4, DPP-2, DPP-8, DPP-9, and fibroblast activation protein-α, more hydrolytic metabolites were found. Among them, DPP-2 had the highest hydrolytic capacity besides DPP-4, and the DPP-4 inhibitor saxagliptin and DPP-2 inhibitor AX8819 can both inhibit the hydrolysis of gliptins. Western blot results showed that DPP-2 and DPP-4 existed in the aforementioned subcellular organelles at varying amounts. In rats, AX8819 decreased the plasma exposures of besigliptin carboxylic acid by 40%. The amide intermediates of gliptins were detected in vivo and in vitro. When the amide derivatives of gliptins were incubated with DPP-4, they were completely hydrolyzed at a rate far more than that from the parent drug, including saxagliptin-amide. Therefore, it was proposed that gliptins, except saxagliptin, were initially hydrolyzed to their amides by DPPs, which was the rate-limiting step in generating the carboxylic end product.
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Affiliation(s)
- Fandi Kong
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China (F.K., X.P., P.D., M.Z., D.Z., X.C.); University of Chinese Academy of Sciences, Beijing, P.R. China (F.K., M.Z., D.Z., X.C.); and School of Life Science and Technology, Shanghai Tech University, Shanghai, P.R. China (J.Z.)
| | - Xiaoyan Pang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China (F.K., X.P., P.D., M.Z., D.Z., X.C.); University of Chinese Academy of Sciences, Beijing, P.R. China (F.K., M.Z., D.Z., X.C.); and School of Life Science and Technology, Shanghai Tech University, Shanghai, P.R. China (J.Z.)
| | - Jihui Zhao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China (F.K., X.P., P.D., M.Z., D.Z., X.C.); University of Chinese Academy of Sciences, Beijing, P.R. China (F.K., M.Z., D.Z., X.C.); and School of Life Science and Technology, Shanghai Tech University, Shanghai, P.R. China (J.Z.)
| | - Pan Deng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China (F.K., X.P., P.D., M.Z., D.Z., X.C.); University of Chinese Academy of Sciences, Beijing, P.R. China (F.K., M.Z., D.Z., X.C.); and School of Life Science and Technology, Shanghai Tech University, Shanghai, P.R. China (J.Z.)
| | - Mingyue Zheng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China (F.K., X.P., P.D., M.Z., D.Z., X.C.); University of Chinese Academy of Sciences, Beijing, P.R. China (F.K., M.Z., D.Z., X.C.); and School of Life Science and Technology, Shanghai Tech University, Shanghai, P.R. China (J.Z.)
| | - Dafang Zhong
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China (F.K., X.P., P.D., M.Z., D.Z., X.C.); University of Chinese Academy of Sciences, Beijing, P.R. China (F.K., M.Z., D.Z., X.C.); and School of Life Science and Technology, Shanghai Tech University, Shanghai, P.R. China (J.Z.)
| | - Xiaoyan Chen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China (F.K., X.P., P.D., M.Z., D.Z., X.C.); University of Chinese Academy of Sciences, Beijing, P.R. China (F.K., M.Z., D.Z., X.C.); and School of Life Science and Technology, Shanghai Tech University, Shanghai, P.R. China (J.Z.)
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Wang YH, Zhang F, Diao H, Wu R. Covalent Inhibition Mechanism of Antidiabetic Drugs—Vildagliptin vs Saxagliptin. ACS Catal 2019. [DOI: 10.1021/acscatal.8b05051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Yong-Heng Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China
| | - Fan Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Hongjuan Diao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Ruibo Wu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
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Rameshrad M, Razavi BM, Ferns GAA, Hosseinzadeh H. Pharmacology of dipeptidyl peptidase-4 inhibitors and its use in the management of metabolic syndrome: a comprehensive review on drug repositioning. ACTA ACUST UNITED AC 2019; 27:341-360. [PMID: 30674032 DOI: 10.1007/s40199-019-00238-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 01/02/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Despite advances in our understanding of metabolic syndrome (MetS) and the treatment of each of its components separately, currently there is no single therapy approved to manage it as a single condition. Since multi-drug treatment increases drug interactions, decreases patient compliance and increases health costs, it is important to introduce single therapies that improve all of the MetS components. EVIDENCE ACQUISITION We conducted a PubMed, Scopus, Google Scholar, Web of Science, US FDA, utdo.ir and clinicaltrial.gov search, gathered the most relevant preclinical and clinical studies that have been published since 2010, and discussed the beneficial effects of dipeptidyl peptidase (DPP)-4 inhibitors to prevent and treat different constituent of the MetS as a single therapy. Furthermore, the pharmacology of DPP-4 inhibitors, focusing on pharmacodynamics, pharmacokinetics, drug interactions and their side effects are also reviewed. RESULTS DPP-4 inhibitors or gliptins are a new class of oral anti-diabetic drugs that seem safe drugs with no severe side effects, commonly GI disturbance, infection and inflammatory bowel disease. They increase mass and function of pancreatic β-cells, and insulin sensitivity in liver, muscle and adipose tissue. It has been noted that gliptin therapy decreases dyslipidemia. DPP-4 inhibitors increase fatty oxidation, and cholesterol efflux, and decrease hepatic triglyceride synthase and de novo lipogenesis. They delay gastric emptying time and lead to satiety. Besides, gliptin therapy has anti-inflammatory and anti-atherogenic impacts, and improves endothelial function and reduces vascular stiffness. CONCLUSION The gathered data prove the efficacy of DPP-4 inhibitors in managing MetS in some levels beyond anti-diabetic effects. This review could be a lead for designing new DPP-4 inhibitors with greatest effects on MetS in future. Introducing drugs with polypharmacologic effects could increase the patient's compliance and decrease the health cost that there is not in multi-drug therapy. Graphical abstract ᅟ.
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Affiliation(s)
- Maryam Rameshrad
- Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Mayfield House, Falmer, Brighton, West Sussex, BN1 9PH, UK
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Padmavathy K, Krishnan KG, Kumar CU, Sathiyaraj E, Sivaramakarthikeyan R, Lim WM, Mai CW, Ramalingan C. Novel acrylamide/acrylonitrile-tethered carbazoles: synthesis, structural, biological, and density functional theory studies. NEW J CHEM 2019; 43:13418-13429. [DOI: 10.1039/c9nj02170a] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The design and synthesis of novel carbazole-based heterocyclic chemical entities as anticancer agents were accomplished.
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Affiliation(s)
- Krishnaraj Padmavathy
- Department of Chemistry
- School of Advanced Sciences (SAS)
- Kalasalingam Academy of Research and Education (Deemed to be University)
- Krishnankoil – 626 126
- India
| | - Kannan Gokula Krishnan
- Department of Chemistry
- School of Advanced Sciences (SAS)
- Kalasalingam Academy of Research and Education (Deemed to be University)
- Krishnankoil – 626 126
- India
| | - Chandran Udhaya Kumar
- Department of Chemistry
- School of Advanced Sciences (SAS)
- Kalasalingam Academy of Research and Education (Deemed to be University)
- Krishnankoil – 626 126
- India
| | - Ethiraj Sathiyaraj
- Department of Chemistry
- School of Advanced Sciences (SAS)
- Kalasalingam Academy of Research and Education (Deemed to be University)
- Krishnankoil – 626 126
- India
| | - Ramar Sivaramakarthikeyan
- Department of Chemistry
- School of Advanced Sciences (SAS)
- Kalasalingam Academy of Research and Education (Deemed to be University)
- Krishnankoil – 626 126
- India
| | - Wei-Meng Lim
- School of Pharmacy, International Medical University
- Bukit Jalil
- Malaysia
| | - Chun-Wai Mai
- School of Pharmacy, International Medical University
- Bukit Jalil
- Malaysia
- Center for Cancer and Stem Cell Research
- Institute for Research
| | - Chennan Ramalingan
- Department of Chemistry
- School of Advanced Sciences (SAS)
- Kalasalingam Academy of Research and Education (Deemed to be University)
- Krishnankoil – 626 126
- India
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Identification of a novel metabolite of vildagliptin in humans: Cysteine targets the nitrile moiety to form a thiazoline ring. Biochem Pharmacol 2018; 156:312-321. [PMID: 30172711 DOI: 10.1016/j.bcp.2018.08.043] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 08/29/2018] [Indexed: 01/01/2023]
Abstract
The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin (VG) is used to treat type 2 diabetes. In rare cases, VG-induced liver injury has been reported. One case report suggested that immune responses were involved in the hepatotoxicity. However, the underlying mechanisms of VG-induced hepatotoxicity are uncertain. In the present study, we investigated whether VG has the potential to covalently bind to macromolecules in cells, a process that could initiate immune-mediated hepatotoxicity. For comparison, M20.7, a major metabolite of VG, and other DPP-4 inhibitors were also evaluated. We found that VG and anagliptin (ANG), which both contain a cyanopyrrolidine moiety, rapidly reacted in non-enzymatic manners on co-incubation with l-cysteine. Both VG and ANG had half-lives of 20-30 min. In contrast, incubation with GSH, rather than l-cysteine, failed to decrease the concentrations of VG or ANG. M20.7, sitagliptin, linagliptin, and alogliptin, having no cyanopyrrolidine moiety, were stable on incubation with l-cysteine or GSH. Structural analysis of the VG- and ANG-cysteine adducts, designated M407 and M487, respectively, revealed that the nitrile moieties of VG and ANG were irreversibly converted to a thiazoline acid. In conclusion, we found that VG and ANG have the potential to covalently bind to a thiol residue of l-cysteine in proteins. Such binding may lead to unpredictable immune responses in humans. l-Cysteine, rather than GSH, would likely be useful to detect the potential for covalent binding that could initiate immune-mediated hepatotoxicity.
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Berger JP, SinhaRoy R, Pocai A, Kelly TM, Scapin G, Gao Y, Pryor KAD, Wu JK, Eiermann GJ, Xu SS, Zhang X, Tatosian DA, Weber AE, Thornberry NA, Carr RD. A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice. Endocrinol Diabetes Metab 2018; 1:e00002. [PMID: 30815539 PMCID: PMC6360916 DOI: 10.1002/edm2.2] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/16/2017] [Indexed: 12/22/2022] Open
Abstract
AIMS Since 2006, DPP-4 inhibitors have become established therapy for the treatment of type 2 diabetes. Despite sharing a common mechanism of action, considerable chemical diversity exists amongst members of the DPP-4 inhibitor class, raising the question as to whether structural differences may result in differentiated enzyme inhibition and antihyperglycaemic activity. METHODS We have compared the binding properties of the most commonly used inhibitors and have investigated the relationship between their inhibitory potency at the level of the enzyme and their acute glucose-lowering efficacy. RESULTS Firstly, using a combination of published crystal structures and in-house data, we demonstrated that the binding site utilized by all of the DPP-4 inhibitors assessed was the same as that used by neuropeptide Y, supporting the hypothesis that DPP-4 inhibitors are able to competitively inhibit endogenous substrates for the enzyme. Secondly, we ascertained that the enzymatic cleft of DPP-4 is a relatively large cavity which displays conformational flexibility to accommodate structurally diverse inhibitor molecules. Finally, we found that for all inhibitors, irrespective of their chemical structure, the inhibition of plasma DPP-4 enzyme activity correlates directly with acute plasma glucose lowering in mice. CONCLUSION The common binding site utilized by different DPP-4 inhibitors enables similar competitive inhibition of the cleavage of the endogenous DPP-4 substrates. Furthermore, despite chemical diversity and a range of binding potencies observed amongst the DPP-4 inhibitors, a direct relationship between enzyme inhibition in the plasma and glucose lowering is evident in mice for each member of the classes studied.
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Affiliation(s)
- Joel P. Berger
- Merck& Co., Inc.KenilworthNJUSA
- Present address:
Takeda Pharmaceuticals International, Inc.CambridgeMAUSA
| | - Ranabir SinhaRoy
- Merck& Co., Inc.KenilworthNJUSA
- Present address:
Janssen Pharmaceuticals, Inc.TitusvilleNJUSA
| | - Alessandro Pocai
- Merck& Co., Inc.KenilworthNJUSA
- Present address:
Janssen Pharmaceuticals, Inc.TitusvilleNJUSA
| | | | | | | | | | | | | | | | | | | | - Ann E. Weber
- Merck& Co., Inc.KenilworthNJUSA
- Present address:
Kallyope Inc.New YorkNYUSA
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Di Lullo L, Mangano M, Ronco C, Barbera V, De Pascalis A, Bellasi A, Russo D, Di Iorio B, Cozzolino M. The treatment of type 2 diabetes mellitus in patients with chronic kidney disease: What to expect from new oral hypoglycemic agents. Diabetes Metab Syndr 2017; 11 Suppl 1:S295-S305. [PMID: 28292575 DOI: 10.1016/j.dsx.2017.03.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 03/03/2017] [Indexed: 02/06/2023]
Abstract
Worldwide, an estimated 200 million people have chronic kidney disease (CKD), whose most common causes include hypertension, arteriosclerosis, and diabetes. About 40% of patients with diabetes develop CKD and intensive blood glucose control through pharmacological intervention can delay CKD progression. Standard therapies for the treatment of type 2 diabetes mellitus include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 2-5) and without dose adjustment. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, are increasingly being used in the treatment of type 2 diabetes; however, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment.
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Affiliation(s)
- Luca Di Lullo
- Department of Nephrology and Dialysis, L. Parodi - Delfino Hospital, Colleferro, Italy.
| | - Michela Mangano
- Department of Health Sciences, S. Paolo Hospital, University of Milan, Italy
| | - Claudio Ronco
- International Renal Research Institute, S. Bortolo Hospital, Vicenza, Italy
| | - Vincenzo Barbera
- Department of Nephrology and Dialysis, L. Parodi - Delfino Hospital, Colleferro, Italy
| | | | - Antonio Bellasi
- Department of Nephrology and Dialysis, ASST Lariana, S. Anna Hospital, Como, Italy
| | - Domenico Russo
- Clinical Nephrology, University Federico II°, Naples, Italy
| | - Biagio Di Iorio
- Department of Nephrology and Dialysis, Landolfi Hospital, Solofra, Italy
| | - Mario Cozzolino
- Department of Health Sciences, S. Paolo Hospital, University of Milan, Italy
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Khojasteh SC, Rietjens IMCM, Dalvie D, Miller G. Biotransformation and bioactivation reactions - 2016 literature highlights. Drug Metab Rev 2017; 49:285-317. [PMID: 28468514 DOI: 10.1080/03602532.2017.1326498] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
We are pleased to present a second annual issue highlighting a previous year's literature on biotransformation and bioactivation. Each contributor to this issue worked independently to review the articles published in 2016 and proposed three to four articles, which he or she believed would be of interest to the broader research community. In each synopsis, the contributing author summarized the procedures, analyses and conclusions as described in the original manuscripts. In the commentary sections, our authors offer feedback and highlight aspects of the work that may not be apparent from an initial reading of the article. To be fair, one should still read the original article to gain a more complete understanding of the work conducted. Most of the articles included in this review were published in Drug Metabolism and Disposition or Chemical Research in Toxicology, but attempts were made to seek articles in 25 other journals. Importantly, these articles are not intended to represent a consensus of the best papers of the year, as we did not want to make any arbitrary standards for this purpose, but rather they were chosen by each author for their notable findings and descriptions of novel metabolic pathways or biotransformations. I am pleased that Drs. Rietjens and Dalvie have again contributed to this annual review. We would like to welcome Grover P Miller as an author for this year's issue, and we thank Tom Baillie for his contributions to last year's edition. We have intentionally maintained a balance of authors such that two come from an academic setting and two come from industry. Finally, please drop us a note if you find this review helpful. We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review. This article is dedicated to Professor Thomas Baillie for his exceptional contributions to the field of drug metabolism.
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Affiliation(s)
- S Cyrus Khojasteh
- a Department of Drug Metabolism and Pharmacokinetics , Genentech, Inc , South San Francisco , CA , USA
| | | | - Deepak Dalvie
- c Drug Metabolism and Pharmacokinetics, Celgene Corporation , San Diego , CA USA
| | - Grover Miller
- d Department of Biochemistry and Molecular Biology , University of Arkansas for Medical Sciences , Little Rock , AR , USA
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Asakura M, Fukami T, Nakajima M, Fujii H, Atsuda K, Itoh T, Fujiwara R. Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo. Drug Metab Dispos 2017; 45:237-245. [PMID: 27895112 DOI: 10.1124/dmd.116.073866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 11/23/2016] [Indexed: 12/24/2022] Open
Abstract
The main route of elimination of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is cyano group hydrolysis to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice coadministered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice. The area under the plasma concentration-time curve (AUC) value of M20.7 in mice coadministered with vildagliptin and sitagliptin was significantly lower than that in mice administered vildagliptin alone (P < 0.01). Although plasma DPP-4 expression level was increased 1.9-fold, hepatic DPP-4 activity was decreased in STZ-induced diabetic mice. The AUC values of M20.7 in STZ-induced diabetic mice were lower than those in control mice (P < 0.01). Additionally, the AUC values of M20.7 significantly positively correlated with hepatic DPP-4 activities in the individual mice (Rs = 0.943, P < 0.05). These findings indicated that DPP-4 greatly contributed to the hydrolysis of vildagliptin in vivo and that not plasma, but hepatic DPP-4 controlled pharmacokinetics of vildagliptin. Furthermore, enzyme assays of 23 individual human liver samples showed that there was a 3.6-fold interindividual variability in vildagliptin-hydrolyzing activities. Predetermination of the interindividual variability of hepatic vildagliptin-hydrolyzing activity might be useful for the prediction of blood vildagliptin concentrations in vivo.
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Affiliation(s)
- Mitsutoshi Asakura
- Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.)
| | - Tatsuki Fukami
- Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.)
| | - Miki Nakajima
- Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.)
| | - Hideaki Fujii
- Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.)
| | - Koichiro Atsuda
- Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.)
| | - Tomoo Itoh
- Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.)
| | - Ryoichi Fujiwara
- Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.)
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Asakura M, Karaki F, Fujii H, Atsuda K, Itoh T, Fujiwara R. Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. Sci Rep 2016; 6:35633. [PMID: 27759084 PMCID: PMC5069476 DOI: 10.1038/srep35633] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 10/03/2016] [Indexed: 01/27/2023] Open
Abstract
Vildagliptin is a potent, orally active inhibitor of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes mellitus. It has been reported that vildagliptin can cause hepatic dysfunction in patients. However, the molecular-mechanism of vildagliptin-induced liver dysfunction has not been elucidated. In this study, we employed an expression microarray to determine hepatic genes that were highly regulated by vildagliptin in mice. We found that pro-inflammatory S100 calcium-binding protein (S100) a8 and S100a9 were induced more than 5-fold by vildagliptin in the mouse liver. We further examined the effects of vildagliptin and its major metabolite M20.7 on the mRNA expression levels of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. In HepG2 cells, vildagliptin, M20.7, and sitagliptin - another DPP-4 inhibitor - induced S100A9 mRNA. In HL-60 cells, in contrast, S100A8 and S100A9 mRNAs were significantly induced by vildagliptin and M20.7, but not by sitagliptin. The release of S100A8/A9 complex in the cell culturing medium was observed in the HL-60 cells treated with vildagliptin and M20.7. Therefore, the parental vildagliptin- and M20.7-induced release of S100A8/A9 complex from immune cells, such as neutrophils, might be a contributing factor of vildagliptin-associated liver dysfunction in humans.
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Affiliation(s)
- Mitsutoshi Asakura
- Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Fumika Karaki
- Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Hideaki Fujii
- Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Koichiro Atsuda
- Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Tomoo Itoh
- Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Ryoichi Fujiwara
- Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan
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An G. Small-Molecule Compounds Exhibiting Target-Mediated Drug Disposition (TMDD): A Minireview. J Clin Pharmacol 2016; 57:137-150. [PMID: 27489162 DOI: 10.1002/jcph.804] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 07/20/2016] [Accepted: 07/30/2016] [Indexed: 01/19/2023]
Abstract
Nonlinearities are commonplace in pharmacokinetics, and 1 special source is the saturable binding of the drug to a high-affinity, low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Compared with large-molecule compounds undergoing TMDD, which has been well recognized due to its high prevalence, TMDD in small-molecule compounds is more counterintuitive and has not been well appreciated. With more and more potent small-molecule drugs acting on highly specific targets being developed as well as increasingly sensitive analytical techniques becoming available, many small-molecule compounds have recently been reported to have nonlinear pharmacokinetics imparted by TMDD. To expand our current knowledge of TMDD in small-molecule compounds and increase the awareness of this clinically important phenomenon, this minireview provides an overview of the small-molecule compounds that demonstrate nonlinear pharmacokinetics imparted by TMDD. The present review also summarizes the general features of TMDD in small-molecule compounds and highlights the differences between TMDD in small-molecule compounds and large-molecule compounds.
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Affiliation(s)
- Guohua An
- Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
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43
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Sekar R, Singh K, Arokiaraj AWR, Chow BKC. Pharmacological Actions of Glucagon-Like Peptide-1, Gastric Inhibitory Polypeptide, and Glucagon. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2016; 326:279-341. [PMID: 27572131 DOI: 10.1016/bs.ircmb.2016.05.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Glucagon family of peptide hormones is a group of structurally related brain-gut peptides that exert their pleiotropic actions through interactions with unique members of class B1 G protein-coupled receptors (GPCRs). They are key regulators of hormonal homeostasis and are important drug targets for metabolic disorders such as type-2 diabetes mellitus (T2DM), obesity, and dysregulations of the nervous systems such as migraine, anxiety, depression, neurodegeneration, psychiatric disorders, and cardiovascular diseases. The current review aims to provide a detailed overview of the current understanding of the pharmacological actions and therapeutic advances of three members within this family including glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon.
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Affiliation(s)
- R Sekar
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - K Singh
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - A W R Arokiaraj
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - B K C Chow
- School of Biological Sciences, University of Hong Kong, Hong Kong, China.
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44
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Davies M, Chatterjee S, Khunti K. The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies. Clin Pharmacol 2016; 8:61-81. [PMID: 27382338 PMCID: PMC4922775 DOI: 10.2147/cpaa.s82008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Worldwide, an estimated 200 million people have chronic kidney disease (CKD), the most common causes of which include hypertension, arteriosclerosis, and diabetes. Importantly, ~40% of patients with diabetes develop CKD, yet evidence from major multicenter randomized controlled trials shows that intensive blood glucose control through pharmacological intervention can reduce the incidence and progression of CKD. Standard therapies for the treatment of type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 2–5) and without dose adjustment; there are contraindications and dose adjustments required for the remaining standard therapies. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, are increasingly being used in the treatment of type 2 diabetes; however, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment. Notably, reductions in albuminuria, a marker of CKD, are observed with many of the drug classes. Dipeptidyl peptidase-IV inhibitors can be used in all stages of renal impairment, with appropriate dose reduction, with the exception of linagliptin, which can be used without dose adjustment. No dose adjustment is required for liraglutide, albiglutide, and dulaglutide in CKD stages 2 and 3, although all glucagon-like peptide-1 receptor agonists are currently contraindicated in stages 4 and 5 CKD. At stage 3 CKD or greater, the sodium-glucose cotransporter-2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) either require dose adjustment or are contraindicated. Ongoing trials, such as CARMELINA, MARLINA, CREDENCE, and CANVAS-R, will help determine the position of these new therapy classes and if they have renoprotective effects in patients with CKD.
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Affiliation(s)
- Melanie Davies
- Diabetes Research Centre, University of Leicester; Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Sudesna Chatterjee
- Diabetes Research Centre, University of Leicester; Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester; Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
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Yamashita Y, Asakura M, Mitsugi R, Fujii H, Nagai K, Atsuda K, Itoh T, Fujiwara R. MicroRNA expression in the vildagliptin-treated two- and three-dimensional HepG2 cells. Drug Metab Pharmacokinet 2016; 31:201-9. [DOI: 10.1016/j.dmpk.2016.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 02/24/2016] [Accepted: 02/24/2016] [Indexed: 12/14/2022]
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Affiliation(s)
- Amar Puttanna
- Department of Diabetes and Endocrinology; City Hospital; Birmingham UK
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Flarakos J, Du Y, Bedman T, Al-Share Q, Jordaan P, Chandra P, Albrecht D, Wang L, Gu H, Einolf HJ, Huskey SE, Mangold JB. Disposition and metabolism of [14C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects. Xenobiotica 2016; 46:986-1000. [DOI: 10.3109/00498254.2015.1014944] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
| | - Yancy Du
- Department of Drug Metabolism and Pharmacokinetics,
| | | | | | - Pierre Jordaan
- Department of Drug Safety & Epidemiology Clinical Development, Novartis Institutes for Biomedical Research, Novartis Pharma, East Hanover, NJ, USA, and
| | - Priya Chandra
- Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, CA, USA
| | | | - Lai Wang
- Department of Drug Metabolism and Pharmacokinetics,
| | - Helen Gu
- Department of Drug Metabolism and Pharmacokinetics,
| | | | - Su-Er Huskey
- Department of Drug Metabolism and Pharmacokinetics,
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Bolleddula J, Chowdhury SK. Carbon-carbon bond cleavage and formation reactions in drug metabolism and the role of metabolic enzymes. Drug Metab Rev 2015; 47:534-57. [PMID: 26390887 DOI: 10.3109/03602532.2015.1086781] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Elimination of xenobiotics from the human body is often facilitated by a transformation to highly water soluble and more ionizable molecules. In general, oxidation-reduction, hydrolysis, and conjugation reactions are common biotransformation reactions that are catalyzed by various metabolic enzymes including cytochrome P450s (CYPs), non-CYPs, and conjugative enzymes. Although carbon-carbon (C-C) bond formation and cleavage reactions are known to exist in plant secondary metabolism, these reactions are relatively rare in mammalian metabolism and are considered exceptions. However, various reactions such as demethylation, dealkylation, dearylation, reduction of alkyl chain, ring expansion, ring contraction, oxidative elimination of a nitrile through C-C bond cleavage, and dimerization, and glucuronidation through C-C bond formation have been reported for drug molecules. Carbon-carbon bond cleavage reactions for drug molecules are primarily catalyzed by CYP enzymes, dimerization is mediated by peroxidases, and C-glucuronidation is catalyzed by UGT1A9. This review provides an overview of C-C bond cleavage and formation reactions in drug metabolism and the metabolic enzymes associated with these reactions.
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Affiliation(s)
- Jayaprakasam Bolleddula
- a Department of Drug Metabolism and Pharmacokinetics , Takeda Pharmaceuticals International Co. , Cambridge , MA , USA
| | - Swapan K Chowdhury
- a Department of Drug Metabolism and Pharmacokinetics , Takeda Pharmaceuticals International Co. , Cambridge , MA , USA
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Nakamura Y, Hasegawa H, Tsuji M, Udaka Y, Mihara M, Shimizu T, Inoue M, Goto Y, Gotoh H, Inagaki M, Oguchi K. Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors. World J Diabetes 2015; 6:840-9. [PMID: 26131325 PMCID: PMC4478579 DOI: 10.4239/wjd.v6.i6.840] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 03/16/2015] [Accepted: 04/01/2015] [Indexed: 02/05/2023] Open
Abstract
Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.
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Garrison KL, Sahin S, Benet LZ. Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS. J Pharm Sci 2015; 104:3229-35. [PMID: 26010239 DOI: 10.1002/jps.24505] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 04/27/2015] [Accepted: 04/28/2015] [Indexed: 01/17/2023]
Abstract
This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters.
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Affiliation(s)
- Kimberly L Garrison
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California
| | - Selma Sahin
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.,Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Leslie Z Benet
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California
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