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Bennani Y, Ben Hassine K, Gencaslan M, Boudal‐Khoshbeen M, Samer C, Ansari M, Daali Y, Satyanarayana Uppugunduri CR. In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting. Pharmacol Res Perspect 2024; 12:e70011. [PMID: 39611692 PMCID: PMC11605732 DOI: 10.1002/prp2.70011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 07/30/2024] [Accepted: 08/06/2024] [Indexed: 11/30/2024] Open
Abstract
UGT2B10 is a phase II drug metabolizing enzyme with limited information on its role in the metabolism of drugs, especially in the pediatric hematopoietic stem cell transplantation setting. Previously, we investigated UGT2B10's role through in silico analyses and prioritized acetaminophen (APAP), lorazepam (LOR), mycophenolic acid (MPA), and voriconazole N-oxide (VCZ N-oxide) for in vitro investigations. In this report, we present in vitro screening of these candidates and of voriconazole (VCZ) to assess their potential to be substrates and/or inhibitors of UGT2B10. Enzyme kinetics experiments included recombinant UGT2B10 and analytical methods based on ultra high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS). To determine potential substrates, candidates were incubated at various therapeutically observed concentrations with recombinant UGT2B10 to identify the corresponding glucuronide metabolite. Inhibition capacity was tested using the selective probe cotinine for its glucuronidation to cotinine N-ß-d-glucuronide. IC50 was determined for compounds exhibiting inhibition. Among the tested compounds, LOR (IC50 = 0.01 μM, R2 = 0.9257) and MPA (IC50 = 0.38 mM, R2 = 0.9212) exhibited inhibition potential for UGT2B10. None of the other tested compounds featured inhibition potential and none of the compounds tested exhibited metabolism through UGT2B10. Further exploration on the clinical relevance of this inhibition using modeling strategies, overlapping nature with other UGT isoforms, and screening other molecules for their inhibition potential on UGT2B10 is warranted.
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Affiliation(s)
- Yahia Bennani
- Division of Clinical Pharmacology and ToxicologyGeneva University HospitalsGenevaSwitzerland
- Geneva Lausanne School of PharmacyUniversity of GenevaGenevaSwitzerland
| | - Khalil Ben Hassine
- Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and ObstetricsUniversity of GenevaGenevaSwitzerland
- Division of Pediatric Oncology and Hematology, Department of Women, Child and AdolescentUniversity Geneva HospitalsGenevaSwitzerland
| | | | - Mary Boudal‐Khoshbeen
- Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and ObstetricsUniversity of GenevaGenevaSwitzerland
- Division of Pediatric Oncology and Hematology, Department of Women, Child and AdolescentUniversity Geneva HospitalsGenevaSwitzerland
| | - Caroline Samer
- Division of Clinical Pharmacology and ToxicologyGeneva University HospitalsGenevaSwitzerland
- Geneva Lausanne School of PharmacyUniversity of GenevaGenevaSwitzerland
- Swiss Center for Applied Human ToxicologyGenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Marc Ansari
- Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and ObstetricsUniversity of GenevaGenevaSwitzerland
- Division of Pediatric Oncology and Hematology, Department of Women, Child and AdolescentUniversity Geneva HospitalsGenevaSwitzerland
| | - Youssef Daali
- Division of Clinical Pharmacology and ToxicologyGeneva University HospitalsGenevaSwitzerland
- Geneva Lausanne School of PharmacyUniversity of GenevaGenevaSwitzerland
- Swiss Center for Applied Human ToxicologyGenevaSwitzerland
- Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Chakradhara Rao Satyanarayana Uppugunduri
- Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and ObstetricsUniversity of GenevaGenevaSwitzerland
- Division of Pediatric Oncology and Hematology, Department of Women, Child and AdolescentUniversity Geneva HospitalsGenevaSwitzerland
- Department of Medical OncologyJawaharlal Institute of Postgraduate Medical Education and ResearchPuducherryIndia
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2
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Babayeva M, Loewy ZG. Cannabis Pharmacogenomics: A Path to Personalized Medicine. Curr Issues Mol Biol 2023; 45:3479-3514. [PMID: 37185752 PMCID: PMC10137111 DOI: 10.3390/cimb45040228] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
Cannabis and related compounds have created significant research interest as a promising therapy in many disorders. However, the individual therapeutic effects of cannabinoids and the incidence of side effects are still difficult to determine. Pharmacogenomics may provide the answers to many questions and concerns regarding the cannabis/cannabinoid treatment and help us to understand the variability in individual responses and associated risks. Pharmacogenomics research has made meaningful progress in identifying genetic variations that play a critical role in interpatient variability in response to cannabis. This review classifies the current knowledge of pharmacogenomics associated with medical marijuana and related compounds and can assist in improving the outcomes of cannabinoid therapy and to minimize the adverse effects of cannabis use. Specific examples of pharmacogenomics informing pharmacotherapy as a path to personalized medicine are discussed.
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Affiliation(s)
- Mariana Babayeva
- Department of Biomedical and Pharmaceutical Sciences, Touro College of Pharmacy, New York, NY 10027, USA
| | - Zvi G Loewy
- Department of Biomedical and Pharmaceutical Sciences, Touro College of Pharmacy, New York, NY 10027, USA
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA
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3
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Milani N, Parrott N, Ortiz Franyuti D, Godoy P, Galetin A, Gertz M, Fowler S. Application of a gut-liver-on-a-chip device and mechanistic modelling to the quantitative in vitro pharmacokinetic study of mycophenolate mofetil. LAB ON A CHIP 2022; 22:2853-2868. [PMID: 35833849 DOI: 10.1039/d2lc00276k] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Microphysiological systems (MPS) consisting of multiple linked organ-on-a-chip (OoC) components are highly promising tools with potential to provide more relevant in vitro to in vivo translation of drug disposition, efficacy and toxicity. A gut-liver OoC system was employed with Caco2 cells in co-culture with HT29 cells in the intestinal compartment and single donor primary hepatocytes in the hepatic compartment for the investigation of intestinal permeability, metabolism (intestinal and hepatic) and potential interplay of those processes. The prodrug mycophenolate mofetil was tested for quantitative evaluation of the gut-liver OoC due to the contribution of both gut and liver in its metabolism. Conversion of mycophenolate mofetil to active drug mycophenolic acid and further metabolism to a glucuronide metabolite was assessed over time in the gut apical, gut basolateral and liver compartments. Mechanistic modelling of experimental data was performed to estimate clearance and permeability parameters for the prodrug, active drug and glucuronide metabolite. Integration of gut-liver OoC data with in silico modelling allowed investigation of the complex combination of intestinal and hepatic processes, which is not possible with standard single tissue in vitro systems. A comprehensive evaluation of the mechanistic model, including structural model and parameter identifiability and global sensitivity analysis, enabled a robust experimental design and estimation of in vitro pharmacokinetic parameters. We propose that similar methodologies may be applied to other multi-organ microphysiological systems used for drug metabolism studies or wherever quantitative knowledge of changing drug concentration with time enables better understanding of biological effect.
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Affiliation(s)
- Nicoló Milani
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
- Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, UK
| | - Neil Parrott
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
| | - Daniela Ortiz Franyuti
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
| | - Patricio Godoy
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
| | - Aleksandra Galetin
- Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, UK
| | - Michael Gertz
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
| | - Stephen Fowler
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
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Liu Y, Zhang H, Li J, Liu L, Wu C, Fu Q, Huang M, Chen X, Wang C, Chen P. Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants. Basic Clin Pharmacol Toxicol 2022; 131:60-73. [PMID: 35567285 DOI: 10.1111/bcpt.13743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/20/2022] [Accepted: 05/10/2022] [Indexed: 11/29/2022]
Abstract
Clinical and genetic influencing factors on free fraction of mycophenolic acid (MPA) have rarely been discussed. The present study investigated whether the clinical and genetic factors could explain the variability in the pharmacokinetics of free MPA (fMPA) and total MPA (tMPA) in Chinese paediatric and adult renal transplant recipients. Twenty-eight paediatric and 31 adult patients were enrolled, and the concentrations of tMPA and fMPA were determined at 0 h (predose) and 0.5, 1, 1.5, 2, 4, 5, 8, 9, 10 and 12 h after mycophenolate mofetil administration. Genetic polymorphisms of UGTs (rs671448, rs1042597, rs2741049, rs62298861, rs7439366, rs12233719) and ABCC2 (rs717620) were simultaneously determined. The clinical and genetic data were analysed and reported. tMPA and fMPA concentrations adjusted for dose per body weight were consistently higher in adults than in paediatric patients. In the paediatric group, only albumin and time after transplantation correlated significantly with the MPA-free fraction variation, which could explain 32.4% of the variability. Besides, ABCC2 polymorphism, albumin and time after transplantation correlated significantly with the MPA-free fraction variation in adults, which could explain 56.9% of the variability. The influencing factors in the paediatric group are different from those in adults, which may be due to age-related transporter expression.
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Affiliation(s)
- Yan Liu
- Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacy, First hospital of Nanchang, Nanchang, China.,Institule of Clinical Pharmacology, School of Pharmaceutical sciences, Sun Yat-sen University, Guangzhou, China
| | - Huanxi Zhang
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Longshan Liu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chenglin Wu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qian Fu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Min Huang
- Institule of Clinical Pharmacology, School of Pharmaceutical sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiao Chen
- Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Changxi Wang
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Pan Chen
- Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Abderahmene A, Ellouz A, Amor D, Ajmi M, Khalij Y, Hamdouni H, Sahtout W, Azzabi A, Omezzine A, Achour A, Bouslama A. The pharmacogenetics of mycophenolate mofetil in Tunisian renal transplant patients. Per Med 2022; 19:383-393. [PMID: 35770851 DOI: 10.2217/pme-2021-0092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: The effects of variants in IMPDH, UGT1A9, UGT1A8, UGT2B7 and SLCO1B1 genes on the efficacy and safety of mycophenolate mofetil (MMF) in the Tunisian population were investigated. Materials & methods: A total of 245 kidney transplant patients being treated with MMF were recruited and cotreated with cyclosporine or tacrolimus. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. MMF, cyclosporine and tacrolimus trough levels were measured by immunoassay. The AUC (AUC0-12hMPA) was estimated by a Bayesian method. Results: In the tacrolimus-treated group, anemia and diarrhea were associated with the UGT1A9-98C and UGT1A9-275T alleles, respectively (p < 0.05). In the cyclosporine-treated group, leukopenia was associated with the SLCO1B1-521T allele (p < 0.05). Both groups had an increased risk of rejection (p < 0.05) associated with the variant alleles of IMPDH2-3757T>C, UGT1A9-2152C>T and UGT1A9-275C>A and the common allele of SLCO1B1-388A>G. However, no significant association was found between the studied genotypes and AUC0-12hMPA or cotreatment levels. Conclusion: The results constitute preliminary evidence for the inclusion of the pharmacogenetics of MMF in kidney pretransplantation evaluations.
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Affiliation(s)
- Amani Abderahmene
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Amel Ellouz
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Dorra Amor
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Marwa Ajmi
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Higher Institute of Biotechnology of Monastir, Street Taher Hadded, 5000, Monastir, Tunisia
| | - Yassine Khalij
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Haithem Hamdouni
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Wissal Sahtout
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Awatef Azzabi
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Asma Omezzine
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Abdellatif Achour
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Ali Bouslama
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.,University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
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6
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Na Takuathung M, Sakuludomkan W, Koonrungsesomboon N. The Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid: Systematic Review and Meta-analysis. Clin Pharmacokinet 2021; 60:1291-1302. [PMID: 34105062 DOI: 10.1007/s40262-021-01037-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Mycophenolic acid (MPA) is among the most commonly prescribed medications for immunosuppression following organ transplantation. Highly variable MPA exposure and drug response are observed among individuals receiving the same dosage of the drug. Identification of candidate genes whose polymorphisms could be used to predict MPA exposure and clinical outcome is of clinical value. OBJECTIVES This study aimed to determine the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of MPA in humans by means of a systematic review and meta-analysis. METHODS A systematic search was conducted on PubMed, EMBASE, Web of Sciences, Scopus, and the Cochrane Library databases. A meta-analysis was conducted to determine any associations between genetic polymorphisms and pharmacokinetic or pharmacodynamic parameters of MPA. Pooled-effect estimates were calculated by means of the random-effects model. RESULTS A total of 37 studies involving 3844 individuals were included in the meta-analysis. Heterozygous carriers of the UGT1A9 -275T>A polymorphism were observed to have a significantly lower MPA exposure than wild-type individuals. Four single nucleotide polymorphisms (SNPs), namely UGT1A9 -2152C>T, UGT1A8 518C>G, UGT2B7 211G>T, and SLCO1B1 521T>C, were also significantly associated with altered MPA pharmacokinetics. However, none of the investigated SNPs, including SNPs in the IMPDH gene, were found to be associated with the clinical efficacy of MPA. The only SNP that was associated with adverse outcomes was SLCO1B3 344T>G. CONCLUSIONS The present systematic review and meta-analysis identified six SNPs that were significantly associated with pharmacokinetic variability or adverse effects of MPA. Our findings represent the basis for future research and clinical implications with regard to the role of pharmacogenetics in MPA pharmacokinetics and drug response.
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Affiliation(s)
- Mingkwan Na Takuathung
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Sriphoom, Muang, Chiang Mai, 50200, Thailand
| | - Wannachai Sakuludomkan
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Sriphoom, Muang, Chiang Mai, 50200, Thailand
| | - Nut Koonrungsesomboon
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Sriphoom, Muang, Chiang Mai, 50200, Thailand.
- Musculoskeletal Science and Translational Research (MSTR) Center, , Chiang Mai University, Muang, Chiang Mai, Thailand.
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7
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Significance of Ethnic Factors in Immunosuppressive Therapy Management After Organ Transplantation. Ther Drug Monit 2021; 42:369-380. [PMID: 32091469 DOI: 10.1097/ftd.0000000000000748] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Clinical outcomes after organ transplantation have greatly improved in the past 2 decades with the discovery and development of immunosuppressive drugs such as calcineurin inhibitors, antiproliferative agents, and mammalian target of rapamycin inhibitors. However, individualized dosage regimens have not yet been fully established for these drugs except for therapeutic drug monitoring-based dosage modification because of extensive interindividual variations in immunosuppressive drug pharmacokinetics. The variations in immunosuppressive drug pharmacokinetics are attributed to interindividual variations in the functional activity of cytochrome P450 enzymes, UDP-glucuronosyltransferases, and ATP-binding cassette subfamily B member 1 (known as P-glycoprotein or multidrug resistance 1) in the liver and small intestine. Some genetic variations have been found to be involved to at least some degree in pharmacokinetic variations in post-transplant immunosuppressive therapy. It is well known that the frequencies and effect size of minor alleles vary greatly between different races. Thus, ethnic considerations might provide useful information for optimizing individualized immunosuppressive therapy after organ transplantation. Here, we review ethnic factors affecting the pharmacokinetics of immunosuppressive drugs requiring therapeutic drug monitoring, including tacrolimus, cyclosporine, mycophenolate mofetil, sirolimus, and everolimus.
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8
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Wang P, Jia Y, Wu R, Chen Z, Yan R. Human gut bacterial β-glucuronidase inhibition: An emerging approach to manage medication therapy. Biochem Pharmacol 2021; 190:114566. [PMID: 33865833 DOI: 10.1016/j.bcp.2021.114566] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 10/21/2022]
Abstract
Bacterial β-glucuronidase enzymes (BGUSs) are at the interface of host-microbial metabolic symbiosis, playing an important role in health and disease as well as medication outcomes (efficacy or toxicity) by deconjugating a large number of endogenous and exogenous glucuronides. In recent years, BGUSs inhibition has emerged as a new approach to manage diseases and medication therapy and attracted an increasing research interest. However, a growing body of evidence underlines great genetic diversity, functional promiscuity and varied inhibition propensity of BGUSs, which have posed big challenges to identifying BGUSs involved in a specific pathophysiological or pharmacological process and developing effective inhibition. In this article, we offered a general introduction of the function, in particular the physiological, pathological and pharmacological roles, of BGUSs and their taxonomic distribution in human gut microbiota, highlighting the structural features (active sites and adjacent loop structures) that affecting the protein-substrate (inhibitor) interactions. Recent advances in BGUSs-mediated deconjugation of drugs and carcinogens and the discovery and applications of BGUS inhibitors in management of medication therapy, typically, irinotecan-induced diarrhea and non-steroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy, were also reviewed. At the end, we discussed the perspectives and the challenges of tailoring BGUS inhibition towards precision medicine.
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Affiliation(s)
- Panpan Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
| | - Yifei Jia
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
| | - Rongrong Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
| | - Zhiqiang Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
| | - Ru Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
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9
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Bergan S, Brunet M, Hesselink DA, Johnson-Davis KL, Kunicki PK, Lemaitre F, Marquet P, Molinaro M, Noceti O, Pattanaik S, Pawinski T, Seger C, Shipkova M, Swen JJ, van Gelder T, Venkataramanan R, Wieland E, Woillard JB, Zwart TC, Barten MJ, Budde K, Dieterlen MT, Elens L, Haufroid V, Masuda S, Millan O, Mizuno T, Moes DJAR, Oellerich M, Picard N, Salzmann L, Tönshoff B, van Schaik RHN, Vethe NT, Vinks AA, Wallemacq P, Åsberg A, Langman LJ. Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2021; 43:150-200. [PMID: 33711005 DOI: 10.1097/ftd.0000000000000871] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022]
Abstract
ABSTRACT When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
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Affiliation(s)
- Stein Bergan
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Kamisha L Johnson-Davis
- Department of Pathology, University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Paweł K Kunicki
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | - Florian Lemaitre
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Rennes, France
| | - Pierre Marquet
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Mariadelfina Molinaro
- Clinical and Experimental Pharmacokinetics Lab, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Ofelia Noceti
- National Center for Liver Tansplantation and Liver Diseases, Army Forces Hospital, Montevideo, Uruguay
| | | | - Tomasz Pawinski
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | | | - Maria Shipkova
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Teun van Gelder
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pathology, Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eberhard Wieland
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jean-Baptiste Woillard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Tom C Zwart
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Markus J Barten
- Department of Cardiac- and Vascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maja-Theresa Dieterlen
- Department of Cardiac Surgery, Heart Center, HELIOS Clinic, University Hospital Leipzig, Leipzig, Germany
| | - Laure Elens
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics (PMGK) Research Group, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Vincent Haufroid
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique, UCLouvain and Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Satohiro Masuda
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Olga Millan
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Dirk J A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Nicolas Picard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | | | - Burkhard Tönshoff
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nils Tore Vethe
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Alexander A Vinks
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Pierre Wallemacq
- Clinical Chemistry Department, Cliniques Universitaires St Luc, Université Catholique de Louvain, LTAP, Brussels, Belgium
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet and Department of Pharmacy, University of Oslo, Oslo, Norway; and
| | - Loralie J Langman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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10
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Klotsman M, Sathyan G, Anderson WH. Single-dose pharmacokinetics of mycophenolic acid following administration of immediate-release mycophenolate mofetil in healthy Beagle dogs. J Vet Pharmacol Ther 2021; 44:650-656. [PMID: 33580714 DOI: 10.1111/jvp.12950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/10/2021] [Accepted: 01/19/2021] [Indexed: 02/06/2023]
Abstract
Mycophenolic acid (MPA) is an immunomodulating agent commonly used in human medicine for the treatment of immune-mediated diseases. There is growing evidence that the immunomodulating properties of mycophenolate mofetil (MMF), a prodrug of MPA, are therapeutically beneficial for the treatment of immune-mediated diseases in dogs. A narrow therapeutic index and high inter-and intra-patient pharmacokinetic (PK) variability complicate the use of MMF. A better characterization of MPA pharmacokinetics is needed to help establish dosing regimens and standardized treatment protocols for canine patients. The purpose of this study was to evaluate the pharmacokinetics of MPA in dogs. MMF oral suspension (10 mg/kg) was administered to five healthy beagle dogs. Serial blood samples were collected from 0 to 18 hours after administration. The simultaneous quantification of MPA, and its metabolites MPA-7-O-glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by liquid chromatography (LC)-mass spectrometry (MS)/MS. MPA peak concentrations were achieved rapidly (median Tmax of 0.5 h). Concentrations fell through 3 hours post-dose and then plateaued around 20% of Cmax. The mean elimination half-life was rapid (5.8 hours) and notable variability was observed in all PK parameters. The PK profiles for the MPAG and AcMPAG metabolites followed a similar pattern as MPA concentration. Future repeat-dose studies will be needed to evaluate steady-state PK parameters and to define therapeutic MPA dose levels.
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Affiliation(s)
| | | | - Wayne H Anderson
- Okava Pharmaceuticals, San Francisco, CA, USA.,Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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11
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Uchiyama K, Saito Y, Takekuma Y, Sugita J, Teshima T, Sugawara M. Pharmacokinetics of mycophenolic acid after haplo-hematopoietic stem cell transplantation in Japanese recipients. J Oncol Pharm Pract 2020; 28:31-38. [PMID: 33349149 DOI: 10.1177/1078155220980815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical-HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. METHODS Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. RESULTS There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. CONCLUSION In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients.
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Affiliation(s)
- Kazuki Uchiyama
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshitaka Saito
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
| | - Yoh Takekuma
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
| | - Junichi Sugita
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Mitsuru Sugawara
- Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.,Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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12
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Sunderland A, Russ G, Sallustio B, Cervelli M, Joyce D, Ooi E, Jeffrey G, Boudville N, Chakera A, Dogra G, Chan D, Wong G, Lim WH. Effect of the proton-pump Inhibitor pantoprazole on MycoPhenolic ACid exposure in kidney and liver transplant recipienTs (IMPACT study): a randomized trial. Nephrol Dial Transplant 2020; 35:1060-1070. [PMID: 32516810 DOI: 10.1093/ndt/gfaa111] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure. METHODS A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study). RESULTS Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group. CONCLUSIONS The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.
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Affiliation(s)
- Andrew Sunderland
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia
| | - Graeme Russ
- Department of Nephrology & Transplantation Services, Royal Adelaide Hospital, and University of Adelaide, Adelaide, Australia
| | - Benedetta Sallustio
- Discipline of Pharmacology, Adelaide Medical School, The University of Adelaide, Adelaide, Australia.,Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Matthew Cervelli
- Department of Pharmacy, Royal Adelaide Hospital, Adelaide, Australia
| | - David Joyce
- School of Biomedical Sciences, University of Western Australia, Perth, Australia.,Biochemistry and Toxicology, PathWest, Perth, Australia.,Faculty of Health and Medical Sciences, Medical School, University of Western Australia, Perth, Australia
| | - Esther Ooi
- School of Biomedical Sciences, University of Western Australia, Perth, Australia.,Faculty of Health and Medical Sciences, Medical School, University of Western Australia, Perth, Australia
| | - Gary Jeffrey
- Faculty of Health and Medical Sciences, Medical School, University of Western Australia, Perth, Australia.,Department of Hepatology Unit, Sir Charles Gairdner Hospital, Perth, Australia
| | - Neil Boudville
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia.,Faculty of Health and Medical Sciences, Medical School, University of Western Australia, Perth, Australia
| | - Aron Chakera
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia
| | - Gursharan Dogra
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia
| | - Doris Chan
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, Australia.,Centre for Transplant and Renal Research, Westmead Hospital, Sydney, Australia.,Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia
| | - Wai H Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia.,Faculty of Health and Medical Sciences, Medical School, University of Western Australia, Perth, Australia
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13
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Docci L, Umehara K, Krähenbühl S, Fowler S, Parrott N. Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuronidation: Lorazepam, Oxazepam, Naloxone, and Zidovudine. AAPS JOURNAL 2020; 22:128. [DOI: 10.1208/s12248-020-00513-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023]
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14
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Tang D, Zhao YC, Liu H, Luo S, Clarke JM, Glass C, Su L, Shen S, Christiani DC, Gao W, Wei Q. Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer. Int J Cancer 2020; 147:1559-1570. [PMID: 32072637 PMCID: PMC8078192 DOI: 10.1002/ijc.32932] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/18/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022]
Abstract
The ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome-wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09-1.36 and p = 0.0003], 0.82 (0.74-0.91 and p = 0.0002) and 1.21 (1.10-1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.
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Affiliation(s)
- Dongfang Tang
- Department of Thoracic Oncology, Huadong Hospital, Fudan University, Shanghai 200040, China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Yu Chen Zhao
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Sheng Luo
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA
| | - Jeffrey M. Clarke
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Carolyn Glass
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Li Su
- Departments of Environmental Health and Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115 USA
| | - Sipeng Shen
- Departments of Environmental Health and Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115 USA
| | - David C. Christiani
- Departments of Environmental Health and Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115 USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Wen Gao
- Department of Thoracic Oncology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA
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15
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Li Y, Xu C, Xu J, Qin Z, Li S, Hu L, Yao Z, Gonzalez FJ, Yao X. Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin-O-glucuronide in HeLa1A1 cells. J Pharm Pharmacol 2020; 72:1771-1786. [DOI: 10.1111/jphp.13324] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/26/2020] [Indexed: 12/11/2022]
Abstract
Abstract
Objectives
Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters.
Methods
Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs.
Key findings
Five phase I metabolites (M1–M5) and three glucuronides (G1–G3) were identified. The CLint values for M4 and G1 by HLM were 127.99 and 1159.07 μl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 μl/min per mg) and CYP2C9 (107.51 μl/min per mg), and UGT1A1 (697.19 μl/min per mg), UGT1A7 (535.78 μl/min per mg), UGT1A8 (247.72 μl/min per mg) and UGT1A9 (783.68 μl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches.
Conclusions
CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.
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Affiliation(s)
- Yang Li
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Chunxia Xu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jinjin Xu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Zifei Qin
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shishi Li
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Liufang Hu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Zhihong Yao
- College of Pharmacy, Jinan University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China
| | - Frank J Gonzalez
- Laboratory of Metabolism, Centre for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Xinsheng Yao
- College of Pharmacy, Jinan University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China
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16
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Wang Z, Wang X, Jia Y, Yin H, Feng Y, Jiang L, Cao J, Liu Y. Inhibition of human UDP‐glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug–drug interactions. Biopharm Drug Dispos 2020; 41:231-238. [DOI: 10.1002/bdd.2241] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 04/25/2020] [Accepted: 04/30/2020] [Indexed: 12/23/2022]
Affiliation(s)
- Zhe Wang
- School of Life and Pharmaceutical SciencesDalian University of Technology Panjin 124221 China
| | - Xiaoyu Wang
- School of Life and Pharmaceutical SciencesDalian University of Technology Panjin 124221 China
| | - Yaqin Jia
- School of Life and Pharmaceutical SciencesDalian University of Technology Panjin 124221 China
| | - Hang Yin
- School of Life and Pharmaceutical SciencesDalian University of Technology Panjin 124221 China
| | - Yuyi Feng
- School of Life and Pharmaceutical SciencesDalian University of Technology Panjin 124221 China
| | - Lili Jiang
- School of Life and Pharmaceutical SciencesDalian University of Technology Panjin 124221 China
| | - Jun Cao
- Department of Occupational and Environmental HealthDalian Medical University Dalian 116044 China
| | - Yong Liu
- School of Life and Pharmaceutical SciencesDalian University of Technology Panjin 124221 China
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17
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Salvadori M, Tsalouchos A. Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy. World J Transplant 2020; 10:90-103. [PMID: 32864355 PMCID: PMC7428791 DOI: 10.5500/wjt.v10.i5.90] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/26/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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18
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Badée J, Fowler S, de Wildt SN, Collier AC, Schmidt S, Parrott N. The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling. Clin Pharmacokinet 2020; 58:189-211. [PMID: 29862468 DOI: 10.1007/s40262-018-0681-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Limited understanding of drug pharmacokinetics in children is one of the major challenges in paediatric drug development. This is most critical in neonates and infants owing to rapid changes in physiological functions, especially in the activity of drug-metabolising enzymes. Paediatric physiologically based pharmacokinetic models that integrate ontogeny functions for cytochrome P450 enzymes have aided our understanding of drug exposure in children, including those under the age of 2 years. Paediatric physiologically based pharmacokinetic models have consequently been recognised by the European Medicines Agency and the US Food and Drug Administration as innovative tools in paediatric drug development and regulatory decision making. However, little is currently known about age-related changes in UDP-glucuronosyltransferase-mediated metabolism, which represents the most important conjugation reaction for xenobiotics. Therefore, the objective of the review was to conduct a thorough literature survey to summarise our current understanding of age-related changes in UDP-glucuronosyltransferases as well as associated clinical and experimental sources of variance. Our findings indicate that there are distinct differences in UDP-glucuronosyltransferase expression and activity between isoforms for different age groups. In addition, there is substantial variability between individuals and laboratories reported for human liver microsomes, which results in part from a lack of standardised experimental conditions. Therefore, we provide a number of best practice recommendations for experimental conditions, which ultimately may help improve the quality of data used for quantitative clinical pharmacology approaches, and thus for safe and effective pharmacotherapy in children.
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Affiliation(s)
- Justine Badée
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA
| | - Stephen Fowler
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Saskia N de Wildt
- Department of Pharmacology and Toxicology, Radboud University, Nijmegen, The Netherlands.,Intensive Care and Department of Paediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Abby C Collier
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Stephan Schmidt
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA
| | - Neil Parrott
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
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19
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Bentata Y. Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them? Artif Organs 2020; 44:561-576. [DOI: 10.1111/aor.13623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/25/2019] [Accepted: 12/20/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Yassamine Bentata
- Nephrology and Kidney Transplantation Unit University Hospital Mohammed VI University Mohammed First Oujda Morocco
- Laboratory of Epidemiology Clinical Research and Public Health Medical School University Mohammed First Oujda Morocco
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20
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Benjanuwattra J, Pruksakorn D, Koonrungsesomboon N. Mycophenolic Acid and Its Pharmacokinetic Drug‐Drug Interactions in Humans: Review of the Evidence and Clinical Implications. J Clin Pharmacol 2019; 60:295-311. [DOI: 10.1002/jcph.1565] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 11/08/2019] [Indexed: 12/14/2022]
Affiliation(s)
| | - Dumnoensun Pruksakorn
- Musculoskeletal Science and Translational Research Center Chiang Mai University Chiang Mai Thailand
- Department of Orthopedics, Faculty of Medicine Chiang Mai University Chiang Mai Thailand
| | - Nut Koonrungsesomboon
- Department of Pharmacology, Faculty of Medicine Chiang Mai University Chiang Mai Thailand
- Musculoskeletal Science and Translational Research Center Chiang Mai University Chiang Mai Thailand
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21
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Colom H, Andreu F, van Gelder T, Hesselink DA, de Winter BCM, Bestard O, Torras J, Cruzado JM, Grinyó JM, Lloberas N. Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach. Clin Pharmacokinet 2019; 57:877-893. [PMID: 29159710 DOI: 10.1007/s40262-017-0603-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND A population pharmacokinetic (PK) protein-binding model was developed to (1) predict free mycophenolic acid (fMPA) based on total MPA (tMPA) concentrations in renal transplant patients, to establish the therapeutic range of fMPA through pharmacokinetic-pharmacodynamic studies; and (2) provide a guideline for dosing mycophenolate mofetil (MMF). METHODS Full PK profiles of 56 patients (from five different occasions) during the first year after transplantation who were treated with oral MMF and cyclosporine, or macrolides (either tacrolimus or sirolimus), were analysed. fMPA protein-binding was modelled using nonlinear mixed effects modelling (NONMEM). The influence of physiological factors and coadministered immunosupressant was studied. RESULTS A two-compartment model with first-order absorption and elimination, linear protein binding and enterohepatic circulation (EHC) best described the PK of MPA. Different recycling rate constants were considered depending on the coadministered immunosuppressant. The protein-binding rate constant (KB [relative standard error, RSE%]) increased nonlinearly with renal function according to K B = 43.1 (3.13)·(CLCR/59.51)0.394(10.66) h-1. Furthermore, fMPA plasma clearance, given by clearance of the free mycophenolic acid (CLfMPA), CLfMPA = 410 (RSE%3.00)·(1+CsA·0.594 (22.39)) L/h, was 59.4% greater in cyclosporine-treated patients than in macrolide-treated patients, leading to lower MPA exposures. External evaluation proved acceptable area under the plasma concentration-time curve and trough concentration predictions. CONCLUSIONS A reliable protein-binding population PK model was developed for prediction of fMPA or tMPA from each other and for dose guiding in stable renal transplant recipients.
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Affiliation(s)
- Helena Colom
- Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Biopharmaceutics and Pharmacokinetics Unit, School of Pharmacy, University of Barcelona, Barcelona, Spain
| | - Franc Andreu
- Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Biopharmaceutics and Pharmacokinetics Unit, School of Pharmacy, University of Barcelona, Barcelona, Spain.,Nephrology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain
| | - Teun van Gelder
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Brenda C M de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Oriol Bestard
- Nephrology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain
| | - Joan Torras
- Nephrology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain
| | - Josep M Cruzado
- Nephrology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain
| | - Josep M Grinyó
- Nephrology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain
| | - Núria Lloberas
- Nephrology Department, Bellvitge University Hospital (IDIBELL), Barcelona, Spain.
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22
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Qin Z, Zhang B, Yang J, Li S, Xu J, Yao Z, Zhang X, Gonzalez FJ, Yao X. The Efflux Mechanism of Fraxetin- O-Glucuronides in UGT1A9-Transfected HeLa Cells: Identification of Multidrug Resistance-Associated Proteins 3 and 4 (MRP3/4) as the Important Contributors. Front Pharmacol 2019; 10:496. [PMID: 31133859 PMCID: PMC6515931 DOI: 10.3389/fphar.2019.00496] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 04/18/2019] [Indexed: 12/26/2022] Open
Abstract
Fraxetin, a natural compound present in many dietary supplements and herbs, is useful in the treatment of acute bacillary dysentery and type 2 diabetes. Previously, several metabolic studies have revealed extensive first-pass metabolism causing formation of fraxetin-O-glucuronides (G1 and G2), resulting in poor bioavailability of fraxetin. Active transport processes play an important role in the excretion of fraxetin-O-glucuronides. Nevertheless, the transporters involved are yet to be elucidated. In this study, we aimed to determine the active efflux transporters, including breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), involved in the excretion of fraxetin-O-glucuronides. A chemical inhibitor, MK571 (5 and 20 μM), a pan-MRP inhibitor, led to a significant decrease in excreted G1 (maximal 59.1%) and G2 levels (maximal 42.4%), whereas Ko143 (5 and 20 μM), a selective BCRP inhibitor, caused moderate downregulation of excreted G1 (maximal 29.4%) and G2 (maximal 28.5%). Furthermore, MRP3 silencing resulted in a marked decrease of excretion rates (by 29.1% for G1 and by 21.1% for G2) and of fraction metabolized (fmet; by 24.1% for G1 and by 18.6% for G2). Similar results, i.e., a significant reduction in excretion rates (by 34.8% for G1 and by 32.3% for G2) and in fmet (by 22.7% for G1 and by 23.1% for G2) were obtained when MRP4 was partially silenced. No obvious modifications in the excretion rates, intracellular levels, and fmet values of glucuronides were observed after short hairpin RNA (shRNA)-mediated silencing of transporters BCRP and MRP1. Taken together, our results indicate that MRP3 and MRP4 contribute more to the excretion of fraxetin-O-glucuronides than the other transporters do.
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Affiliation(s)
- Zifei Qin
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Beibei Zhang
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jing Yang
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Shishi Li
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jinjin Xu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Zhihong Yao
- College of Pharmacy, Jinan University, Guangzhou, China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China
| | - Xiaojian Zhang
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Xinsheng Yao
- College of Pharmacy, Jinan University, Guangzhou, China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China
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23
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Kiang TKL, Partovi N, Shapiro RJ, Berman JM, Collier AC, Ensom MHH. Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients. Clin Drug Investig 2018; 38:1011-1022. [DOI: 10.1007/s40261-018-0694-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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24
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Meng HY, Luo ZH, Hu B, Jin WL, Yan CK, Li ZB, Xue YY, Liu Y, Luo YE, Xu LQ, Yang H. SNPs affecting the clinical outcomes of regularly used immunosuppressants. Pharmacogenomics 2018. [PMID: 29517418 DOI: 10.2217/pgs-2017-0182] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent studies have suggested that genomic diversity may play a key role in different clinical outcomes, and the importance of SNPs is becoming increasingly clear. In this article, we summarize the bioactivity of SNPs that may affect the sensitivity to or possibility of drug reactions that occur among the signaling pathways of regularly used immunosuppressants, such as glucocorticoids, azathioprine, tacrolimus, mycophenolate mofetil, cyclophosphamide and methotrexate. The development of bioinformatics, including machine learning models, has enabled prediction of the proper immunosuppressant dosage with minimal adverse drug reactions for patients after organ transplantation or for those with autoimmune diseases. This article provides a theoretical basis for the personalized use of immunosuppressants in the future.
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Affiliation(s)
- Huan-Yu Meng
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Zhao-Hui Luo
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Bo Hu
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Wan-Lin Jin
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Cheng-Kai Yan
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Zhi-Bin Li
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Yuan-Yuan Xue
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Yu Liu
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Yi-En Luo
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Li-Qun Xu
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
| | - Huan Yang
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, PR China
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25
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He BX, Qiao B, Lam AKY, Zhao XL, Zhang WZ, Liu H. Association between UDP-glucuronosyltransferase 2B7 tagSNPs and breast cancer risk in Chinese females. Clin Exp Pharmacol Physiol 2018; 45:437-443. [PMID: 29272031 DOI: 10.1111/1440-1681.12908] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 11/18/2017] [Accepted: 12/06/2017] [Indexed: 01/10/2023]
Affiliation(s)
- Bao-Xia He
- Department of Pharmacy; Affiliated Cancer Hospital of Zhengzhou University; Zhengzhou China
| | - Bin Qiao
- Department of Stomatology; The First Affiliated Hospital of Zhengzhou University; Zhengzhou China
| | - Alfred King-Yin Lam
- Cancer Molecular Pathology; School of Medicine; Menzies Health Institute Queensland; Griffith University; Gold Coast QLD Australia
| | - Xiu-Li Zhao
- Department of Pharmacy; Affiliated Cancer Hospital of Zhengzhou University; Zhengzhou China
| | - Wen-Zhou Zhang
- Department of Pharmacy; Affiliated Cancer Hospital of Zhengzhou University; Zhengzhou China
| | - Hui Liu
- Department of Breast Surgery; Affiliated Cancer Hospital of Zhengzhou University; Zhengzhou China
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26
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Effects of UGT2B7 Genetic Polymorphisms on Serum Concentrations of Valproic Acid in Chinese Children With Epilepsy Comedicated With Lamotrigine. Ther Drug Monit 2017; 38:343-9. [PMID: 26717295 DOI: 10.1097/ftd.0000000000000271] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Valproic acid (VPA) is widely used in the treatment of children with epilepsy. Genetic polymorphisms in genes encoding drug-metabolizing enzymes may be an important source of interindividual variability in VPA metabolism. VPA is a substrate of uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7). In this study, we seek to evaluate the effects of genetic polymorphisms of the UGT2B7 gene on serum VPA concentrations in epileptic children comedicated with lamotrigine (LTG). METHODS We recruited 166 Chinese children with epilepsy who were treated with VPA in combination with LTG. Serum VPA and LTG concentrations were measured by fluorescence polarization immunoassay and high performance liquid chromatography, respectively. The UGT2B7 -161C > T in the 5'-upstream regions and 211 G > T, 372A > G, 735A > G, and 802C > T in the coding regions were genotyped using polymerase chain reaction amplification followed by direct automated DNA sequencing. RESULTS Our data show that patients carrying the variant UGT2B7 -161C > T or 802C > T genotypes had significantly higher adjusted VPA concentrations than those carrying the wild-type genotypes. The significant associations were potentiated after adjusted by age and adjusted LTG concentration. However, no associations were detected between the other studied UGT2B7 genotypes and adjusted VPA concentrations, even after adjusting by age and comedication. CONCLUSIONS These results suggest that the UGT2B7 -161C > T or 802C > T mutations affect VPA pharmacokinetics, which are potentially enhanced by age and concomitant LTG administration. These findings provide a potential mechanism underlying interindividual variation in the disposition of VPA in combination with LTG.
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27
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Iemsupakkul P, Kongchareonsombat W, Kijvikai K. Comparison of Pfannenstiel or Extended Iliac Port Site Kidney Extraction in Laparoscopic Donor Nephrectomy: Do We Have Consensus? EXP CLIN TRANSPLANT 2017; 16:466-472. [PMID: 28338459 DOI: 10.6002/ect.2017.0017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Our objective was to compare the outcomes of the different extraction sites between extended iliac port site incision and Pfannenstiel incision during laparoscopic donor nephrectomy. MATERIALS AND METHODS We prospectively evaluated patients who underwent laparoscopic donor nephrectomy from June 2014 to March 2015 at our institution. Perioperative parameters were included, with particular reference to warm ischemic time. The other parameters recorded included operative time, blood loss, hospital stay, analgesic requirement, and cosmetic results. RESULTS We analyzed a total of 41 patients. Kidney retrieval site of each patient was made randomly. Extraction sites were done by using extended iliac port site incisions in 23 patients and by Pfannenstiel incision in 18 patients. Mean warm ischemic time was 4.09 minutes with extended iliac port site incision versus 4.94 minutes with Pfannenstiel incision (P = .04). Mean operative time, blood loss, hospital stay, and analgesic requirements were comparable between the 2 groups. Mean cosmetic score was 10.39 with extended iliac port site versus 12.06 with Pfannenstiel incision. CONCLUSIONS Extraction with extended iliac port site incision had significantly less warm ischemic time than Pfannenstiel incision in laparoscopic donor nephrectomy. It was also not inferior to Pfannenstiel incision regarding the other.
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Affiliation(s)
- Paiboon Iemsupakkul
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
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28
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The regioselective glucuronidation of morphine by dimerized human UGT2B7, 1A1, 1A9 and their allelic variants. Acta Pharmacol Sin 2017; 38:1184-1194. [PMID: 28552915 DOI: 10.1038/aps.2016.157] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 11/14/2016] [Indexed: 12/21/2022]
Abstract
Uridine diphosphate-glucuronosyltransferase (UGT) 2B7 is expressed mostly in the human liver, lung and kidney and can transfer endogenous glucuronide group into its substrate and impact the pharmacological effects of several drugs such as estriol, AZT and morphine. UGT2B7 and its allelic variants can dimerize with the homologous enzymes UGT1A1 and UGT1A9, as well as their allelic variants, and then change their enzymatic activities in the process of substrate catalysis. The current study was designed to identify this mechanism using morphine as the substrate of UGT2B7. Single-recombinant allozymes, including UGT2B7*1 (wild type), UGT2B7*71S (A71S, 211G>T), UGT2B7*2 (H268Y, 802C>T), UGT2B7*5 (D398N, 1192G>A), and double-recombinant allozymes formed by the dimerization of UGT1A9*1 (wild type), UGT1A9*2 (C3Y, 8G>A), UGT1A9*3 (M33T, 98T>C), UGT1A9*5 (D256N, 766G>A), UGT1A1 (wild type) with its splice variant UGT1A1b were established and incubated with morphine in vitro. Each sample was analyzed with HPLC-MS/MS. All enzyme kinetic parameters were then measured and analyzed. From the results, the production ratio of its aberrant metabolism and subsequent metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), changes regioselectively. Double-recombinant allozymes exhibit stronger enzymatic activity catalyzing morphine than the single-recombinant alloyzymes. Compared to UGT2B7*1, UGT2B7*2 singles or doubles have lower Km values for M3G and M6G, whereas UGT2B7*5 allozymes perform opposite effects. The double allozymes of UGT1A9*2 or UGT1A9*5 with UGT2B7 tend to produce M6G. Interestingly, the majority of single or double allozymes significantly reduce the ratio of M3G to M6G. The UGT1A9*2-UGT2B7*1 double enzyme has the lowest M3G:M6G ratio, reflecting that more M6G would form in morphine glucuronide metabolism. This study demonstrates that UGT2B7 common SNPs and their dimers with UGT1A1 and UGT1A9 and their allelic variants can regioselectively affect the generation of two metabolites of morphine via altering the CLint ratios of M3G to M6G. These results may predict the effectiveness of morphine antinociception in individualized opioid treatment.
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29
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Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach. Biochem Pharmacol 2017; 137:93-106. [PMID: 28433553 DOI: 10.1016/j.bcp.2017.04.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 04/13/2017] [Indexed: 11/23/2022]
Abstract
Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 1A expression by microRNAs (miRNAs) may be an important mechanism underlying interindividual variability in drug glucuronidation. Furthermore, the UGT1A 3'-UTR shared by all UGT1A enzymes is polymorphic, containing three linked SNPs (rs10929303, rs1042640, and rs8330) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT1A expression through binding to the reference and/or common variant UGT1A 3'-UTR. Luciferase reporter plasmids containing either the reference or variant UGT1A 3'-UTR were screened against a 2048 human miRNA library to identify those miRNAs that decrease luciferase activity by at least 30% when co-transfected into HEK293 cells. Four novel miRNAs (miR-103b, miR-141-3p, miR-200a-3p, and miR-376b-3p) were identified that repressed both reference and variant UGT1A 3'-UTR, while two other miRNAs selectively repressed the reference (miR-1286) or variant (miR-21-3p) 3'-UTR. Deletion and mutagenesis studies confirmed the binding site location for each miRNA. rs8330 disrupted miR-1286 binding to the reference UGT1A 3'-UTR, while rs10929303 enhanced miR-21-3p binding to the variant 3'-UTR. Transfection of miR-21-3p, miR-103b, miR-141-3p, miR-200a-3p, and miR-376b-3p mimics into LS180 human intestinal cells showed repression of UGT1A1 and UGT1A6 mediated glucuronidation and mRNA without affecting UGT2B7 activity or mRNA. Furthermore, transfection of miR-21-3p, miR-141-3p, and miR-200a-3p into primary human hepatocytes, repressed UGT1A1 activity and mRNA without affecting CYP3A activity. Finally, miR-21-3p and miR-200a-3p expression were negatively correlated with UGT1A6 activity and mRNA in human liver samples. Thus, UGT1A is regulated by multiple miRNAs with some showing allele-dependent effects.
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Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation. Ther Drug Monit 2016; 38 Suppl 1:S1-20. [PMID: 26977997 DOI: 10.1097/ftd.0000000000000287] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.
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Girard-Bock C, Benoit-Biancamano MO, Villeneuve L, Desjardins S, Guillemette C. A Rare UGT2B7 Variant Creates a Novel N-Glycosylation Site at Codon 121 with Impaired Enzyme Activity. Drug Metab Dispos 2016; 44:1867-1871. [PMID: 27612916 DOI: 10.1124/dmd.116.071860] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 09/08/2016] [Indexed: 02/13/2025] Open
Abstract
The UDP glucuronosyltransferase (UGT) superfamily comprises glycoproteins that reside in the endoplasmic reticulum membranes and that undergo post-translational modifications (PTMs). UGT2B7 is of particular interest because of its action on a wide variety of drugs. Most studies currently survey common variants and examine only a small fraction of the genetic diversity; however, rare variants (frequency <1%) might have a significant effect because they are predicted to greatly outnumber common variants in the human genome. We discovered a rare single nucleotide UGT2B7 variant of potential pharmacogenetic relevance that encodes a nonconservative amino acid substitution at codon 121. This low-frequency variation, found in two individuals of a population of 305 healthy volunteers, leads to the translation of an asparagine instead of an aspartic acid (UGT2B7 p.D121N). This amino acid change was predicted to create a putative N-glycosylation motif NX(S/T) subsequently validated upon endoglycosidase H treatment of microsomal fractions and inhibition of N-glycosylation of endogenously produced UGT2B7 with tunicamycin in human embryonic kidney (HEK293) cells. The presence of an additional N-linked glycan on the UGT2B7 enzyme, likely affecting proper protein folding, resulted in a significant decrease of 49% and 40% in the formation of zidovudine and mycophenolic acid glucuronides, respectively. A systematic survey of the Short Genetic Variations database uncovered 32 rare, naturally occurring missense variations predicted to create or disrupt N-glycosylation sequence motifs in the other UGT2B enzymes. Collectively, these variants have the potential to increase the proportion of variance explained in the UGT pathway resulting from changes in PTMs, such as N-linked glycosylation with consequences on drug metabolism.
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Affiliation(s)
- Camille Girard-Bock
- Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
| | - Marie-Odile Benoit-Biancamano
- Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
| | - Lyne Villeneuve
- Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
| | - Sylvie Desjardins
- Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
| | - Chantal Guillemette
- Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec City (C.G.B., L.V., S.D., C.G.), and Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, (M.O.B.B.), Québec, Canada
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Wang X, Wang H, Shen B, Overholser BR, Cooper BR, Lu Y, Tang H, Zhou C, Sun X, Zhong L, Favus MJ, Decker BS, Liu W, Peng Z. 1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10. Transl Res 2016; 178:54-62.e6. [PMID: 27496319 DOI: 10.1016/j.trsl.2016.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 05/31/2016] [Accepted: 07/07/2016] [Indexed: 11/18/2022]
Abstract
Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity.
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Affiliation(s)
- Xiaoliang Wang
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China; Department of Medicinal Chemistry & Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Ind, USA
| | - Hongwei Wang
- Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, Ill, USA
| | - Bing Shen
- Department of Urology, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Brian R Overholser
- Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, Ind, USA
| | - Bruce R Cooper
- Bindley Bioscience Center, Metabolite Profiling Facility, Purdue University, West Lafayette, Ind, USA
| | - Yinghao Lu
- Department of Hematology, Affiliated Hospital of Guiyang Medical College, The Hematopoietic Stem Cell Transplant Center of Guizhou Province, Guiyang, P. R. China
| | - Huamei Tang
- Department of Pathology, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Chongzhi Zhou
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Xing Sun
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Lin Zhong
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Murray J Favus
- Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, Ill, USA
| | - Brian S Decker
- Division of Nephrology, School of Medicine, Indiana University, Indianapolis, Ind, USA; Department of Medicine, School of Medicine, Indiana University, Indianapolis, Ind, USA
| | - Wanqing Liu
- Department of Medicinal Chemistry & Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Ind, USA.
| | - Zhihai Peng
- Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China.
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Yuan LM, Gao ZZ, Sun HY, Qian SN, Xiao YS, Sun LL, Zeng S. Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9, and 2B7 and Impacts on Glucuronidation Activity. Sci Rep 2016; 6:34450. [PMID: 27857056 PMCID: PMC5114717 DOI: 10.1038/srep34450] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/13/2016] [Indexed: 11/24/2022] Open
Abstract
Human UDP-glucuronosyltransferases (UGTs) play a pivotal role in phase II metabolism by catalyzing the glucuronidation of endobiotics and xenobiotics. The catalytic activities of UGTs are highly impacted by both genetic polymorphisms and oligomerization. The present study aimed to assess the inter-isoform hetero-dimerization of UGT1A1, 1A9, and 2B7, including the wild type (1A1*1, 1A9*1, and 2B7*1) and the naturally occurring (1A1*1b, 1A9*2/*3/*5, and 2B7*71S/*2/*5) variants. The related enzymes were double expressed in Bac-to-Bac systems. The fluorescence resonance energy transfer (FRET) technique and co-immunoprecipitation (Co-IP) revealed stable hetero-dimerization of UGT1A1, 1A9, and 2B7 allozymes. Variable FRET efficiencies and donor-acceptor distances suggested that genetic polymorphisms resulted in altered affinities to the target protein. In addition, the metabolic activities of UGTs were differentially altered upon hetero-dimerization via double expression systems. Moreover, protein interactions also changed the regioselectivity of UGT1A9 for querectin glucuronidation. These findings provide in-depth understanding of human UGT dimerization as well as clues for complicated UGT dependent metabolism in humans.
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Affiliation(s)
- Ling-Min Yuan
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zhang-Zhao Gao
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Hong-Ying Sun
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Sai-Nan Qian
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yong-Sheng Xiao
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Lian-Li Sun
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
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Thijs JL, Van Der Geest BAM, Van Der Schaft J, Van Den Broek MP, Van Seggelen WO, Bruijnzeel-Koomen CAF, Hijnen DJ, Van Schaik RH, De Bruin-Weller MS. Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis. J DERMATOL TREAT 2016; 28:242-245. [PMID: 27549213 DOI: 10.1080/09546634.2016.1227420] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93-80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage.
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Affiliation(s)
- J L Thijs
- a Department of Dermatology and Allergology
| | | | | | | | | | | | - D J Hijnen
- a Department of Dermatology and Allergology
| | - R H Van Schaik
- c Department of Clinical Chemistry and Hematology , University Medical Center Utrecht , Utrecht , the Netherlands.,d Department of Clinical Chemistry , Erasmus University Medical Center Rotterdam , Rotterdam , the Netherlands
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Tian DD, Yuan JJ, Ren YL, Guo XG, Zhang W, Zhang LR, Kan QC. UGT1A9 Single Nucleotide Polymorphisms do not Account for the Variability of Response to Propofol: A One-way Design with Multiple Levels Study of the Propofol Pharmacodynamics. INT J PHARMACOL 2016. [DOI: 10.3923/ijp.2016.401.407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Brian W, Tremaine LM, Arefayene M, de Kanter R, Evers R, Guo Y, Kalabus J, Lin W, Loi CM, Xiao G. Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG. Pharmacogenomics 2016; 17:615-31. [PMID: 27045656 DOI: 10.2217/pgs.16.9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition.
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Affiliation(s)
- William Brian
- Sanofi, Translational Medicine and Early Development, 55 Corporate Drive, Bridgewater, NJ 08807, USA
| | - Larry M Tremaine
- Pfizer Inc., Worldwide Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, Eastern Point Road, Groton, CT 06340, USA
| | - Million Arefayene
- Biogen, Early Development Sciences, 14 Cambridge Center, Cambridge, MA 02142, USA
| | - Ruben de Kanter
- Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
| | - Raymond Evers
- Merck & Co, Pharmacodynamics, Pharmacokinetics and Drug Metabolism, 2000 Galloping Hill Road, Kenilworth, NJ07033, USA
| | - Yingying Guo
- Eli Lilly and Company, Drug Disposition, LillyCorporate Center, Indianapolis, IN 46285, USA
| | - James Kalabus
- Novartis Pharmaceuticals, 1 Health Plaza, EastHanover, NJ 07936, USA
| | - Wen Lin
- Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics, One Health Plaza, East Hanover, NJ07936-1080, USA
| | - Cho-Ming Loi
- Pfizer Inc., Worldwide Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism,10646 Science Center Drive, San Diego, CA 92121, USA
| | - Guangqing Xiao
- Biogen, Preclinical PK and In vitro ADME, 14 Cambridge Center, Cambridge, MA 02142, USA
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Pharmacogenetic Biomarkers Predictive of the Pharmacokinetics and Pharmacodynamics of Immunosuppressive Drugs. Ther Drug Monit 2016; 38 Suppl 1:S57-69. [DOI: 10.1097/ftd.0000000000000255] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Ma CL, Jiao Z, Wu XY, Hong Z, Wu ZY, Zhong MK. Association between PK/PD-involved gene polymorphisms and carbamazepine-individualized therapy. Pharmacogenomics 2015; 16:1499-512. [PMID: 26314341 DOI: 10.2217/pgs.15.94] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Aim: To evaluate the association between the major genetic variants involved in the pharmacokinetic/pharmacodynamic (PK/PD) properties of carbamazepine (CBZ) and its maintenance doses and concentrations. Patients & methods: The genotypes of 166 patients receiving CBZ monotherapy were detected using high-resolution melting curve (HRM) and TaqMan methods. Results: Both univariate and multiple regression analyses revealed that carriers of the SCN1A IVS5–91G>A or EPHX1 c.337T>C allele tended to require a higher CBZ dose and a lower CBZ natural logarithmic concentration–dose ratio (lnCDR) than noncarriers (p < 0.05). Furthermore, two interactions between these genes were associated with the lnCDR and the maintenance dosage of CBZ, respectively. Conclusion: SCN1A IVS5–91G>A gene polymorphism is potential genetic biomarker associated with the PK of CBZ.
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Affiliation(s)
- Chun-Lai Ma
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Zheng Jiao
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Xun-Yi Wu
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhen Hong
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhi-Yuan Wu
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Ming-Kang Zhong
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
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Sun H, Ma Z, Lu D, Wu B. Regio- and Isoform-Specific Glucuronidation of Psoralidin: Evaluation of 3- O -Glucuronidation as a Functional Marker for UGT1A9. J Pharm Sci 2015; 104:2369-77. [DOI: 10.1002/jps.24464] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 03/17/2015] [Accepted: 04/08/2015] [Indexed: 01/05/2023]
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Francke S, Mamidi RNVS, Solanki B, Scheers E, Jadwin A, Favis R, Devineni D. In vitro metabolism of canagliflozin in human liver, kidney, intestine microsomes, and recombinant uridine diphosphate glucuronosyltransferases (UGT) and the effect of genetic variability of UGT enzymes on the pharmacokinetics of canagliflozin in humans. J Clin Pharmacol 2015; 55:1061-72. [PMID: 25827774 DOI: 10.1002/jcph.506] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
O-glucuronidation is the major metabolic elimination pathway for canagliflozin. The objective was to identify enzymes and tissues involved in the formation of 2 major glucuronidated metabolites (M7 and M5) of canagliflozin and subsequently to assess the impact of genetic variations in these uridine diphosphate glucuronosyltransferases (UGTs) on in vivo pharmacokinetics in humans. In vitro incubations with recombinant UGTs revealed involvement of UGT1A9 and UGT2B4 in the formation of M7 and M5, respectively. Although M7 and M5 were formed in liver microsomes, only M7 was formed in kidney microsomes. Participants from 7 phase 1 studies were pooled for pharmacogenomic analyses. A total of 134 participants (mean age, 41 years; men, 63%; white, 84%) were included in the analysis. In UGT1A9*3 carriers, exposure of plasma canagliflozin (Cmax,ss , 11%; AUCτ,ss , 45%) increased relative to the wild type. An increase in exposure of plasma canagliflozin (Cmax,ss , 21%; AUCt,ss , 18%) was observed in participants with UGT2B4*2 genotype compared with UGT2B4*2 noncarriers. Metabolites further delineate the role of both enzymes. The pharmacokinetic findings in participants carrying the UGT1A9*3 and UGT2B4*2 allele implicate that UGT1A9 and UGT2B4 are involved in the metabolism of canagliflozin to M7 and M5, respectively.
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Affiliation(s)
| | | | | | - Ellen Scheers
- Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Andrew Jadwin
- Janssen Research & Development, LLC, Raritan, NJ, USA
| | - Reyna Favis
- Janssen Research & Development, LLC, Raritan, NJ, USA
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41
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Xie XC, Li J, Wang HY, Li HL, Liu J, Fu Q, Huang JW, Zhu C, Zhong GP, Wang XD, Sun PP, Huang M, Wang CX, Li JL. Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients. Acta Pharmacol Sin 2015; 36:644-50. [PMID: 25864649 DOI: 10.1038/aps.2015.7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 02/12/2015] [Indexed: 12/25/2022]
Abstract
AIM To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients. METHODS A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 -1818T>C, I399C>T, -118T9/10, -440C>T, -331T>C, UGT2B7 IVS1+985A>G, 211G>T, -900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics. RESULTS The dose-adjusted MPA AUC0-12 h of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC0-12 h of the patients with the UGT1A7 622CC and UGT1A9 -440CT/-331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and -440C/-331T homozygotes. Furthermore, the genotypes UGT1A9 -1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC0-12 h. CONCLUSION The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.
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The effects of drugs with immunosuppressive or immunomodulatory activities on xenobiotics-metabolizing enzymes expression in primary human hepatocytes. Toxicol In Vitro 2015; 29:1088-99. [PMID: 25929522 DOI: 10.1016/j.tiv.2015.04.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/02/2015] [Accepted: 04/22/2015] [Indexed: 11/22/2022]
Abstract
In this paper we investigated the effects of several drugs used in transplant medicine, i.e. cyclosporine A, tacrolimus, rapamycin, everolimus, mycophenolate mofetil, fluvastatin and rosuvastatin, on the expression of major drug-metabolizing enzymes in human hepatocytes. Moreover, we tested the ability of these drugs to affect transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon receptor (AhR). We found that most of tested compounds did not induce expression of CYP1A1/1A2/3A4/2A6/2B6/2C9 mRNAs in human hepatocytes. Slight induction was observed for CYP2A6/2C9 mRNAs and CYP2A6 protein in the rapamycin-treated hepatocytes. Decrease of CYP2A6 and CYP2B6 proteins was observed in rosuvastatin-treated cells. Mycophenolate mofetil antagonized the effects of dexamethasone on GR but it potentiated the action of dioxin on AhR. Induction of CYP1A1 mRNA in HepG2 cells by dioxin was modestly antagonized by mycophenolate mofetil, while the induction by benzo[a]pyren or S-omeprazole was significantly potentiated by this drug. In general, tested compounds can be considered safe in the terms of possible drug-drug interaction caused by induction of drug-metabolizing cytochromes P450. Nevertheless, mycophenolate mofetil is of possible concern and its combination with drugs, environmental pollutants or food constituents, which activate AhR, may represent a significant toxicological risk.
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Chen S, Laverdiere I, Tourancheau A, Jonker D, Couture F, Cecchin E, Villeneuve L, Harvey M, Court MH, Innocenti F, Toffoli G, Lévesque E, Guillemette C. A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients. THE PHARMACOGENOMICS JOURNAL 2015; 15:513-20. [PMID: 25778466 DOI: 10.1038/tpj.2015.12] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 12/03/2014] [Accepted: 01/28/2015] [Indexed: 12/13/2022]
Abstract
The risk of severe irinotecan-induced neutropenia has been shown to be related to the UGT1 variant UGT1A1*28, which increases exposure to the potent metabolite SN-38. Our goal was to identify a novel UGT1 marker(s) using 28 haplotype-tagged single nucleotide polymorphisms genotyped by mass spectrometry. By characterizing the UGT1 sequence from a cohort of 167 Canadian metastatic colorectal cancer (mCRC) patients and a validation cohort of 250 Italian mCRC patients, we found rs11563250G, located in the intergenic region downstream of UGT1, to be significantly associated with reduced risk of severe neutropenia (odds ratio (OR)=0.21; P=0.043 and OR=0.27; P=0.036, respectively, and OR=0.31 when combined; P=0.001), which remained significant upon correction for multiple testing in the combined cohort (P=0.041). For the two-marker haplotype rs11563250G and UGT1A1*1 (rs8175347 TA6), the OR was of 0.17 (P=0.0004). Genetic testing of this marker may identify patients who might benefit from increased irinotecan dosing.
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Affiliation(s)
- S Chen
- Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada
| | - I Laverdiere
- Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada
| | - A Tourancheau
- Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada
| | - D Jonker
- Division of Medical Oncology, Department of Medicine, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
| | - F Couture
- Centre Hospitalier Universitaire de Québec Research Center and Faculty of Medicine, Laval University, Québec, Québec, Canada
| | - E Cecchin
- Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Cancer for Molecular Biomedicine, Aviano, Italy
| | - L Villeneuve
- Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada
| | - M Harvey
- Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada
| | - M H Court
- Individualized Medicine Program, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, WA, USA
| | - F Innocenti
- Division of Pharmacotherapy & Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
| | - G Toffoli
- Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Cancer for Molecular Biomedicine, Aviano, Italy
| | - E Lévesque
- Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada.,Centre Hospitalier Universitaire de Québec Research Center and Faculty of Medicine, Laval University, Québec, Québec, Canada
| | - C Guillemette
- Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada
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Personalization of the immunosuppressive treatment in renal transplant recipients: the great challenge in "omics" medicine. Int J Mol Sci 2015; 16:4281-305. [PMID: 25690039 PMCID: PMC4346957 DOI: 10.3390/ijms16024281] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/04/2015] [Accepted: 02/09/2015] [Indexed: 12/25/2022] Open
Abstract
Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.
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Pithukpakorn M, Tiwawanwong T, Lalerd Y, Assawamakin A, Premasathian N, Tasanarong A, Thongnoppakhun W, Vongwiwatana A. Mycophenolic acid AUC in Thai kidney transplant recipients receiving low dose mycophenolate and its association with UGT2B7 polymorphisms. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2014; 7:379-85. [PMID: 25540593 PMCID: PMC4270037 DOI: 10.2147/pgpm.s72760] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Background Despite use of a lower mycophenolate dose in Thai kidney transplant patients, acceptable graft and patient outcomes can be achieved. We therefore examined the pharmacokinetics of mycophenolic acid (MPA) by area under the curve (AUC) and investigated genetic contribution in mycophenolate metabolism in this population. Methods Kidney transplant recipients with stable graft function who were receiving mycophenolate mofetil 1,000 mg/d in combination with either cyclosporine or tacrolimus, and prednisolone were studied. The MPA concentration was measured by fluorescence polarization immunoassay (FPIA), at predose and 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing. Genetic polymorphisms in UGT1A8, UGT1A9, and UGT2B7 were examined by denaturing high-performance liquid chromatography (DHPLC)-based single-base extension (SBE) analysis. Results A total 138 patients were included in study. The mean AUC was 39.49 mg-h/L (28.39–89.58 mg-h/L), which was in the therapeutic range. The correlation between the predose MPA concentration and AUC was poor. The mean AUC in the tacrolimus group was higher than that in the cyclosporine group. Polymorphisms in UGT2B7 showed significant association with AUC. Conclusion Most of our patients with reduced mycophenolate dose had the AUC within the therapeutic range. Genetic polymorphisms in UGT2B7 may play a role in MPA metabolism in Thai kidney transplant patients.
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Affiliation(s)
| | - Tiwat Tiwawanwong
- Division of Nephrology, Department of Medicine, Mahidol University, Bangkok, Thailand
| | - Yupaporn Lalerd
- Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Anunchai Assawamakin
- Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand ; Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Nalinee Premasathian
- Division of Nephrology, Department of Medicine, Mahidol University, Bangkok, Thailand
| | - Adis Tasanarong
- Department of Medicine, Faculty of Medicine, Thammasat University, Bangkok, Thailand
| | - Wanna Thongnoppakhun
- Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Attapong Vongwiwatana
- Division of Nephrology, Department of Medicine, Mahidol University, Bangkok, Thailand
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Population pharmacokinetics of mycophenolic acid and its main glucuronide metabolite: a comparison between healthy Chinese and Caucasian subjects receiving mycophenolate mofetil. Eur J Clin Pharmacol 2014; 71:95-106. [PMID: 25327506 DOI: 10.1007/s00228-014-1771-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 10/08/2014] [Indexed: 01/30/2023]
Abstract
PURPOSE Mycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is widely used for prophylaxis of solid organ transplant rejection. MPA is primarily metabolized to 7-O-mycophenolic acid glucuronide (MPAG), an inactive metabolite that undergoes enterohepatic recirculation (EHC). This study assessed ethnic differences in the pharmacokinetics (PK) of MPA and MPAG between healthy Chinese and Caucasian subjects using population PK analysis. METHODS Data were pooled from 132 healthy subjects (80 Chinese, 52 Caucasians) in eight clinical studies in which MMF was administered in a single oral dose. Population PK analysis was performed using NONMEM®. RESULTS The PK of MPA and MPAG were best described by a five-chain compartment model, including a gallbladder compartment for EHC and a transit absorption model. Ethnicity was significantly correlated with the apparent clearance (CL/F) and volume of distribution (V/F) of MPAG but not those of MPA. Weight was identified as a covariate and was correlated with the PK of MPA and MPAG. MPA CL/F was 11.5 L/h for a 70-kg healthy subject, and the MPAG CL/F values were 1.36 and 1.90 L/h for 70-kg Chinese and Caucasian individuals, respectively. Internal and external evaluation indicated model validity. CONCLUSIONS This is the first population PK analysis to evaluate ethnic differences in the PK of MPA and MPAG in healthy Chinese and Caucasian subjects. No differences were observed in the PK of MPA between healthy Chinese and Caucasian subjects. Although, the MPAG CL/F was approximately 40 % higher in Caucasians, this finding may not be clinically relevant.
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Recipient Uridine 5′-Diphospho-glucuronosyltransferase UGT1A9 c.98T>C Variant Determines Transplanted Kidney Filtration Rate. Transplant Proc 2014; 46:2678-82. [DOI: 10.1016/j.transproceed.2014.09.077] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Tian X, Liang S, Wang C, Wu B, Ge G, Deng S, Liu K, Yang L, Ma X. Regioselective glucuronidation of andrographolide and its major derivatives: metabolite identification, isozyme contribution, and species differences. AAPS JOURNAL 2014; 17:156-66. [PMID: 25204783 DOI: 10.1208/s12248-014-9658-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 08/21/2014] [Indexed: 01/16/2023]
Abstract
Andrographolide (AND) and two of its derivatives, deoxyandrographolide (DEO) and dehydroandrographolide (DEH), are widely used in clinical practice as anti-inflammatory agents. However, UDP-glucuronosyltransferase (UGT)-mediated phase II metabolism of these compounds is not fully understood. In this study, glucuronidation of AND, DEO, and DEH was characterized using liver microsomes and recombinant UGT enzymes. We isolated six glucuronides and identified them using 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. We also systematically analyzed various kinetic parameters (K m, V max, and CLint) for glucuronidation of AND, DEO, and DEH. Among 12 commercially available UGT enzymes, UGT1A3, 1A4, 2B4, and 2B7 exhibited metabolic activities toward AND, DEO, and DEH. Further, UGT2B7 made the greatest contribution to glucuronidation of all three anti-inflammatory agents. Regioselective glucuronidation showed considerable species differences. 19-O-Glucuronides were present in liver microsomes from all species except rats. 3-O-Glucuronides were produced by pig and cynomolgus monkey liver microsomes for all compounds, and 3-O-glucuronide of DEH was detected in mouse and rat liver microsomes (RLM). Variations in K m values were 48.6-fold (1.93-93.6 μM) and 49.5-fold (2.01-99.1 μM) for 19-O-glucuronide and 3-O-glucuronide formation, respectively. Total intrinsic clearances (CLint) for 3-O- and 19-O-glucuronidation varied 4.8-fold (22.7-110 μL min(-1) mg(-1)), 10.6-fold (94.2-991 μL min(-1) mg(-1)), and 8.3-fold (122-1,010 μL min(-1) mg(-1)), for AND, DEH, and DEO, respectively. Our results indicate that UGT2B7 is the major UGT enzyme involved in the metabolism of AND, DEO, and DEH. Metabolic pathways in the glucuronidation of AND, DEO, and DEH showed considerable species differences.
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Affiliation(s)
- Xiangge Tian
- College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
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Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients. Eur J Clin Pharmacol 2014; 70:1211-9. [DOI: 10.1007/s00228-014-1728-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 08/01/2014] [Indexed: 01/06/2023]
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50
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Li P, Shuker N, Hesselink DA, van Schaik RHN, Zhang X, van Gelder T. Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients? Transpl Int 2014; 27:994-1004. [PMID: 24963914 DOI: 10.1111/tri.12382] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 04/22/2014] [Accepted: 06/17/2014] [Indexed: 01/01/2023]
Affiliation(s)
- Pengmei Li
- Department of Hospital Pharmacy; Erasmus Medical Center Rotterdam; Rotterdam The Netherlands
- Department of Pharmacy; China-Japan Friendship Hospital; Beijing China
| | - Nauras Shuker
- Department of Hospital Pharmacy; Erasmus Medical Center Rotterdam; Rotterdam The Netherlands
- Department of Internal Medicine; Erasmus Medical Center Rotterdam; Rotterdam The Netherlands
| | - Dennis A. Hesselink
- Department of Internal Medicine; Erasmus Medical Center Rotterdam; Rotterdam The Netherlands
| | - Ron H. N. van Schaik
- Department of Clinical Chemistry; Erasmus Medical Center Rotterdam; Rotterdam The Netherlands
| | - Xianglin Zhang
- Department of Pharmacy; China-Japan Friendship Hospital; Beijing China
| | - Teun van Gelder
- Department of Hospital Pharmacy; Erasmus Medical Center Rotterdam; Rotterdam The Netherlands
- Department of Internal Medicine; Erasmus Medical Center Rotterdam; Rotterdam The Netherlands
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