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Bouchghoul H, Bouyer J, Senat MV, Mandelbrot L, Letourneau A, Bourcigaux N, Becquemont L, Verstuyft C. Hypoglycemia and Glycemic Control With Glyburide in Women With Gestational Diabetes and Genetic Variants of Cytochrome P450 2C9 and/or OATP1B3. Clin Pharmacol Ther 2021; 110:141-148. [PMID: 33341937 DOI: 10.1002/cpt.2142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 11/25/2020] [Indexed: 01/21/2023]
Abstract
Glyburide is mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme and enters the liver via the transporter OATP1B3. The variants OATP1B3*4 (699 G>A; rs7311358) and CYP2C9*2 and *3 are known to have a significant influence on the hepatic uptake and metabolism of glyburide, with lower clearance than in the wild type. In an ancillary study of the INDAO trial, we selected 117 pregnant women with gestational diabetes treated by glyburide and assessed the role of the combined CYP2C9 and OATP1B3 genetic polymorphisms in hypoglycemia and glycemic control. Three groups were constituted: (1) the wild-type genotype group (wild-type allele genotype for both CYP2C9*1 and OATP1B3*1 (699G)), (2) the intermediate group (carriers of CYP2C9*2 allele or OATP1B3*4 (699G>A) heterozygous), and (3) the variant group (carriers of CYP2C9*3 allele and/or OATP1B3*4 (699G>A) homozygous variant). We found that the risk of hypoglycemia was significantly higher in the variant genotype at the second week of treatment: 20.0% (4/20) vs. 8.1% (3/37) in the intermediate group and 4.1% (2/49) in the wild-type genotype group (P = 0.03). The last daily dose of glyburide during pregnancy was lower for patients in the variant genotype group: 4.7 mg (SD 3.5) vs. 8.7 mg (SD 5.7) in the wild-type group and 5.7 mg (SD 3.7) in the intermediate group (P < 0.01). In conclusion, the no-function variants CYP2C9*3 and OATP1B3*4 are associated with a higher risk of hypoglycemia and a lower dose of glyburide in women with gestational diabetes treated with glyburide, which is consistent with the pharmacokinetic roles of both CYP2C9 and OATP1B3.
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Affiliation(s)
- Hanane Bouchghoul
- Department of Gynecology-Obstetrics, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France.,CESP, Université Paris-Saclay, UVSQ, Inserm, Villejuif, France
| | - Jean Bouyer
- CESP, Université Paris-Saclay, UVSQ, Inserm, Villejuif, France
| | - Marie-Victoire Senat
- Department of Gynecology-Obstetrics, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France.,CESP, Université Paris-Saclay, UVSQ, Inserm, Villejuif, France
| | - Laurent Mandelbrot
- Department of Gynecology and Obstetrics, Assistance Publique-Hôpitaux de Paris, Louis Mourier Hospital, Colombes, France
| | - Alexandra Letourneau
- Department of Gynecology and Obstetrics, Assistance Publique-Hôpitaux de Paris, Antoine Béclère Hospital, Clamart, France
| | - Nathalie Bourcigaux
- Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, St Antoine Hospital Paris, Paris, France
| | - Laurent Becquemont
- CESP, Université Paris-Saclay, UVSQ, Inserm, Villejuif, France.,Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Paris, France
| | - Céline Verstuyft
- CESP, Université Paris-Saclay, UVSQ, Inserm, Villejuif, France.,Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Paris, France
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Ju G, Yan K, Xu Y, Chen S, Zheng Z, Qiu W. Evaluation of Bioequivalency and Pharmacokinetic Parameters for Two Formulations of Glimepiride 1-mg in Chinese Subjects. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2637-2644. [PMID: 32753845 PMCID: PMC7351633 DOI: 10.2147/dddt.s249355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/09/2020] [Indexed: 11/23/2022]
Abstract
Purpose Glimepiride, an FDA-approved oral hypoglycemic drug, is a long-acting sulfonylurea (SU), used for treating type 2 diabetes. The study aimed to evaluate the bioequivalence and safety profiles of two different formulations of glimepiride 1 mg from two different manufactures in healthy Chinese subjects in the fasting and fed state in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation. Patients and Methods This study is an open-label, two-period, two-sequence, randomized, two-way crossover pharmacokinetic study in healthy Chinese subjects in the fasting and fed state. Seventy-two subjects were randomly assigned to the fasting group and the fed group (n=36 each). We collected blood samples, 24-h post drug administration. The plasma concentration of glimepiride was assessed using HPLC coupled with mass spectrometry. The following parameters were evaluated: AUC0-inf, AUC0-last, Cmax, t1⁄2, Tmax, and λz. Safety was determined based on the occurrence of adverse events (AEs) and laboratory examinations (biochemistry, hematology, and urinalysis) throughout the entire study period. Results The geometric mean ratios (GMR) amongst the two glimepiride formulations for the primary pharmacokinetic parameters, ie, AUC0-inf, AUC0-last, and Cmax as well as the corresponding 90% CIs, were all within the range of 80.00-125.00% in the fasting and fed state. The safety profile for both treatments was comparable. Conclusion PK analysis revealed that the test and reference formulations of glimepiride were bioequivalent and well tolerated in healthy Chinese subjects. Chinese Clinical Trials Registry identifier: CTR20171121. Clinical Trial Registration Number CTR20171121.
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Affiliation(s)
- Gehang Ju
- School of Pharmacy Lanzhou University, Lanzhou University, Lanzhou, People's Republic of China
| | - Keyu Yan
- School of Pharmacy Lanzhou University, Lanzhou University, Lanzhou, People's Republic of China
| | - Youwei Xu
- Research Institute, Shandong Xinhua Pharmaceutical Company Limited, Shandong, People's Republic of China
| | - Shilin Chen
- The Department of Analysis, Chengdu Fanweixi Pharmaceutical Technology Company, Limited, Chengdu, People's Republic of China
| | - Zhonghui Zheng
- Research Institute, Shandong Xinhua Pharmaceutical Company Limited, Shandong, People's Republic of China
| | - Wen Qiu
- Phase I Clinical Unit, Lanzhou University Second Hospital, Lanzhou, People's Republic of China
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Pearson ER. Diabetes: Is There a Future for Pharmacogenomics Guided Treatment? Clin Pharmacol Ther 2020; 106:329-337. [PMID: 31012484 PMCID: PMC6771467 DOI: 10.1002/cpt.1484] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 04/09/2019] [Indexed: 12/21/2022]
Abstract
Diabetes is a disease defined on the basis of hyperglycemia. There are monogenic forms of diabetes where defining the genetic cause has a dramatic impact on treatment—with patients being able to transition from insulin to sulfonylureas. However, the majority of diabetes is type 2 diabetes. This review outlines the robust evidence accrued to date for pharmacogenetics of metformin, sulfonylureas, thiazolidinediones, and dipeptidyl peptidase‐4 inhibitors but highlights that these variants will only be of clinical utility when the genotype is already known at the point of prescribing. The future of pharmacogenetics in diabetes and other common complex disease relies on a paradigm shift—that of preemptive panel genotyping and use of clinical decision support tools to assimilate this genetic information with other clinical phenotypic data and to present this information simply to the prescriber. Given the recent dramatic fall in genotyping costs, this future is not far off.
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Affiliation(s)
- Ewan R Pearson
- Division of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK
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Mannino GC, Andreozzi F, Sesti G. Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine. Diabetes Metab Res Rev 2019; 35:e3109. [PMID: 30515958 PMCID: PMC6590177 DOI: 10.1002/dmrr.3109] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/27/2018] [Accepted: 11/30/2018] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control, it is often necessary to rely on combination therapy of multiple drugs or insulin because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several antihyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics. Pharmacogenetics is the branch of genetics that investigates how our genome influences individual responses to drugs, therapeutic outcomes, and incidence of adverse effects. In this review, we evaluated the pharmacogenetic evidences currently available in the literature, and we identified the top informative genetic variants associated with response to the most common anti-diabetic drugs: metformin, DPP-4 inhibitors/GLP1R agonists, thiazolidinediones, and sulfonylureas/meglitinides. Overall, we found 40 polymorphisms for each drug class in a total of 71 loci, and we examined the possibility of encouraging genetic screening of these variants/loci in order to critically implement decision-making about the therapeutic approach through precision medicine strategies. It is possible then to anticipate that when the clinical practice will take advantage of the genetic information of the diabetic patients, this will provide a useful resource for the prevention of T2DM progression, enabling the identification of the precise drug that is most likely to be effective and safe for each patient and the reduction of the economic impact on a global scale.
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Affiliation(s)
- Gaia Chiara Mannino
- Department of Medical and Surgical SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly
| | - Francesco Andreozzi
- Department of Medical and Surgical SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly
| | - Giorgio Sesti
- Department of Medical and Surgical SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly
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Kim CO, Oh ES, Kim H, Park MS. Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions? DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:503-512. [PMID: 28260863 PMCID: PMC5330189 DOI: 10.2147/dddt.s129586] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration–time curve during the dose interval at steady state (AUCτ,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism.
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Affiliation(s)
- Choon Ok Kim
- Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Eun Sil Oh
- Department of Pharmaceutical Medicine and Regulatory Sciences, College of Medicine and Pharmacy, Yonsei University, Incheon
| | - Hohyun Kim
- Korea Medicine Research Institute, Inc., Seongnam
| | - Min Soo Park
- Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul; Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
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Dawed AY, Zhou K, Pearson ER. Pharmacogenetics in type 2 diabetes: influence on response to oral hypoglycemic agents. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2016; 9:17-29. [PMID: 27103840 PMCID: PMC4827904 DOI: 10.2147/pgpm.s84854] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is one of the leading causes of morbidity and mortality, consuming a significant proportion of public health spending. Oral hypoglycemic agents (OHAs) are the frontline treatment approaches after lifestyle changes. However, huge interindividual variation in response to OHAs results in unnecessary treatment failure. In addition to nongenetic factors, genetic factors are thought to contribute to much of such variability, highlighting the importance of the potential of pharmacogenetics to improve therapeutic outcome. Despite the presence of conflicting results, significant progress has been made in an effort to identify the genetic markers associated with pharmacokinetics, pharmacodynamics, and ultimately therapeutic response and/or adverse outcomes to OHAs. As such, this article presents a comprehensive review of current knowledge on pharmacogenetics of OHAs and provides insights into knowledge gaps and future directions.
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Affiliation(s)
- Adem Yesuf Dawed
- Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK
| | - Kaixin Zhou
- Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK
| | - Ewan Robert Pearson
- Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK
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Abstract
The introduction of several new drug groups into the treatment of type 2 diabetes in the past few decades leads to an increased requirement for an individualized treatment approach. A personalized treatment is important from the point of view of both efficacy and safety. Recent guidelines are based mainly on entirely phenotypic characteristics such as diabetes duration, presence of macrovascular complications, or risk of hypoglycemia with the use of individual drugs. So far, genetic knowledge is used to guide treatment in the monogenic forms of diabetes. With the accumulating pharmacogenetic evidence in type 2 diabetes, there are reasonable expectations that genetics might help in the adjustment of drug doses to reduce severe side effects, as well as to make better therapeutic choices among the drugs available for the treatment of diabetes.
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Affiliation(s)
- Ivan Tkáč
- Department of Internal Medicine 4, P. J. Šafárik University, Faculty of Medicine, L. Pasteur University Hospital, Rastislavova 43, 041 90, Košice, Slovakia,
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An UPLC–MS/MS method for the analysis of glimepiride and fluoxetine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2015; 980:16-9. [DOI: 10.1016/j.jchromb.2014.12.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 12/12/2014] [Accepted: 12/20/2014] [Indexed: 11/21/2022]
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Brunetti A, Brunetti FS, Chiefari E. Pharmacogenetics of type 2 diabetes mellitus: An example of success in clinical and translational medicine. World J Transl Med 2014; 3:141-149. [DOI: 10.5528/wjtm.v3.i3.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 09/25/2014] [Accepted: 11/03/2014] [Indexed: 02/05/2023] Open
Abstract
The pharmacological interventions currently available to control type 2 diabetes mellitus (T2DM) show a wide interindividual variability in drug response, emphasizing the importance of a personalized, more effective medical treatment for each individual patient. In this context, a growing interest has emerged in recent years and has focused on pharmacogenetics, a discipline aimed at understanding the variability in patients’ drug response, making it possible to predict which drug is best for each patient and at what doses. Recent pharmacological and clinical evidences indicate that genetic polymorphisms (or genetic variations) of certain genes can adversely affect drug response and therapeutic efficacy of oral hypoglycemic agents in patients with T2DM, through pharmacokinetic- and/or pharmacodynamic-based mechanisms that may reduce the therapeutic effects or increase toxicity. For example, genetic variants in genes encoding enzymes of the cytochrome P-450 superfamily, or proteins of the ATP-sensitive potassium channel on the beta-cell of the pancreas, are responsible for the interindividual variability of drug response to sulfonylureas in patients with T2DM. Instead, genetic variants in the genes that encode for the organic cation transporters of metformin have been related to changes in both pharmacodynamic and pharmacokinetic responses to metformin in metformin-treated patients. Thus, based on the individual’s genotype, the possibility, in these subjects, of a personalized therapy constitutes the main goal of pharmacogenetics, directly leading to the development of the right medicine for the right patient. Undoubtedly, this represents an integral part of the translational medicine network.
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10
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Impact of CYP2C9*3/*3 genotype on the pharmacokinetics and pharmacodynamics of oxicam NSAIDs. Pharmacogenet Genomics 2014; 24:406-7. [PMID: 25003537 DOI: 10.1097/fpc.0000000000000064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Response to Suarez-Kurtz's comments on strongly increased exposure of meloxicam in CYP2C9*3/*3 individuals. Pharmacogenet Genomics 2014; 24:407-8. [PMID: 25003538 DOI: 10.1097/fpc.0000000000000070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Varma MVS, Scialis RJ, Lin J, Bi YA, Rotter CJ, Goosen TC, Yang X. Mechanism-based pharmacokinetic modeling to evaluate transporter-enzyme interplay in drug interactions and pharmacogenetics of glyburide. AAPS JOURNAL 2014; 16:736-48. [PMID: 24839071 DOI: 10.1208/s12248-014-9614-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Accepted: 04/26/2014] [Indexed: 11/30/2022]
Abstract
The purpose of this study is to characterize the involvement of hepato-biliary transport and cytochrome-P450 (CYP)-mediated metabolism in the disposition of glyburide and predict its pharmacokinetic variability due to drug interactions and genetic variations. Comprehensive in vitro studies suggested that glyburide is a highly permeable drug with substrate affinity to multiple efflux pumps and to organic anion transporting polypeptide (OATP)1B1 and OATP2B1. Active hepatic uptake was found to be significantly higher than the passive uptake clearance (15.8 versus 5.3 μL/min/10(6)-hepatocytes), using the sandwich-cultured hepatocyte model. In vitro, glyburide is metabolized (intrinsic clearance, 52.9 μL/min/mg-microsomal protein) by CYP3A4, CYP2C9, and CYP2C8 with fraction metabolism of 0.53, 0.36, and 0.11, respectively. Using these in vitro data, physiologically based pharmacokinetic models, assuming rapid-equilibrium between blood and liver compartments or permeability-limited hepatic disposition, were built to describe pharmacokinetics and evaluate drug interactions. Permeability-limited model successfully predicted glyburide interactions with rifampicin and other perpetrator drugs. Conversely, model assuming rapid-equilibrium mispredicted glyburide interactions, overall, suggesting hepatic uptake as the primary rate-determining process in the systemic clearance of glyburide. Further modeling and simulations indicated that the impairment of CYP2C9 function has a minimal effect on the systemic exposure, implying discrepancy in the contribution of CYP2C9 to glyburide clearance.
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Affiliation(s)
- Manthena V S Varma
- Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA,
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Wang Z, Wang L, Xia M, Ji Y, Xu RA. WITHDRAWN: Simultaneous determination of glimepiride and fluoxetine in human plasma by ultra performance liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2014. [DOI: 10.1016/j.jchromb.2014.04.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Becker ML, Pearson ER, Tkáč I. Pharmacogenetics of oral antidiabetic drugs. Int J Endocrinol 2013; 2013:686315. [PMID: 24324494 PMCID: PMC3845331 DOI: 10.1155/2013/686315] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 10/28/2013] [Accepted: 10/28/2013] [Indexed: 02/08/2023] Open
Abstract
Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants in CYP2C9, ABCC8/KCNJ11, and TCF7L2 were associated with the effect of sulfonylureas. CYP2C9 encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9, ABCC8 and KCNJ11 genes encode proteins constituting ATP-sensitive K(+) channel which is a therapeutic target for sulfonylureas, and TCF7L2 is a gene with the strongest association with type 2 diabetes. SLC22A1, SLC47A1, and ATM gene variants were repeatedly associated with the response to metformin. SLC22A1 and SLC47A1 encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant near ATM gene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity of CTRB1/2 gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future.
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Affiliation(s)
- Matthijs L. Becker
- Department of Epidemiology, Erasmus MC, 3015 CE Rotterdam, The Netherlands
- Pharmacy Foundation of Haarlem Hospitals, 2035 RC Haarlem, The Netherlands
| | - Ewan R. Pearson
- Medical Research Institute, University of Dundee, Dundee DD1 9SY, UK
| | - Ivan Tkáč
- Department of Internal Medicine 4, Faculty of Medicine, P. J. Šafárik University, 041 80 Košice, Slovakia
- Department of Internal Medicine 4, L. Pasteur University Hospital, Rastislavova 43, 041 90 Košice, Slovakia
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van Leeuwen N, Swen JJ, Guchelaar HJ, ’t Hart LM. The Role of Pharmacogenetics in Drug Disposition and Response of Oral Glucose-Lowering Drugs. Clin Pharmacokinet 2013; 52:833-54. [PMID: 23719679 DOI: 10.1007/s40262-013-0076-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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17
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Mannino GC, Sesti G. Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data. Mol Diagn Ther 2013; 16:285-302. [PMID: 23018631 DOI: 10.1007/s40291-012-0002-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, abnormally elevated hepatic glucose production, and reduced glucose-stimulated insulin secretion. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary for many patients, in order to restore acceptable glycemic control and to reduce the risk of development and progression of disease complications. Notably, even patients who appear to have similar requirements of antidiabetic regimens show great variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects during treatment. Pharmacogenomics is a promising area of investigation and involves the search for genetic polymorphisms that may explain the interindividual variability in antidiabetic therapy response. The initial positive results portend that genomic efforts will be able to shed important light on variability in pharmacologic traits. In this review, we summarize the current understanding of genetic polymorphisms that may affect the responses of subjects with T2DM to antidiabetic treatment. These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the cytochrome P450 [CYP] superfamily, the organic anion transporting polypeptide [OATP] family, and the polyspecific organic cation transporter [OCT] family); genes encoding drug targets and receptors (including peroxisome proliferator-activated receptor gamma [PPARG], the adenosine triphosphate [ATP]-sensitive potassium channel [K(ATP)], and incretin receptors); and genes involved in the causal pathway of T2DM that are able to modify the effects of drugs (including adipokines, transcription factor 7-like 2 (T cell specific, HMG-box) [TCF7L2], insulin receptor substrate 1 [IRS1], nitric oxide synthase 1 (neuronal) adaptor protein [NOS1AP], and solute carrier family 30 (zinc transporter), member 8 [SLC30A8]). In addition to these three major classes, we also review the available evidence on novel genes (CDK5 regulatory subunit associated protein 1-like 1 [CDKAL1], insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2], potassium voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1], paired box 4 [PAX4] and neuronal differentiation 1 [NEUROD1] transcription factors, ataxia telangiectasia mutated [ATM], and serine racemase [SRR]) that have recently been proposed as possible modulators of therapeutic response in subjects with T2DM.
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Affiliation(s)
- Gaia Chiara Mannino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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Gökalp O, Gunes A, Cam H, Cure E, Aydın O, Tamer MN, Scordo MG, Dahl ML. Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting. Eur J Clin Pharmacol 2011; 67:1223-1229. [PMID: 21691805 DOI: 10.1007/s00228-011-1078-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2011] [Accepted: 05/31/2011] [Indexed: 02/07/2023]
Abstract
AIM To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. METHODS One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods. RESULTS Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (< 70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles (*2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed (P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks. CONCLUSIONS CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide.
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Affiliation(s)
- Osman Gökalp
- Medical Faculty, Department of Pharmacology, Dicle University, Diyarbakir, Turkey
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Population pharmacokinetic analysis of glimepiride with CYP2C9 genetic polymorphism in healthy Korean subjects. Eur J Clin Pharmacol 2011; 67:889-98. [PMID: 21476064 DOI: 10.1007/s00228-011-1035-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Accepted: 03/07/2011] [Indexed: 10/18/2022]
Abstract
PURPOSE The purpose of this study was to develop a population pharmacokinetic (PPK) model of glimepiride and to investigate the influence of genetic polymorphisms in CYP2C9 on the PPK of glimepiride in healthy Korean subjects. METHODS Serum data after a single oral dose of 2 mg of glimepiride in 177 healthy male Korean subjects (CYP2C9*1*1: 163 subjects, *1/*3: 14 subjects) were used. We estimated the PPK of glimepiride using a nonlinear mixed effects modeling (NONMEM) method and explored the possible influence of genetic polymorphisms in CYP2C9 on the PPK of glimepiride. RESULTS The disposition of glimepiride was best described with a two-compartment model with a Weibull-type absorption and first-order elimination. The visual predictive check indicated that the pharmacokinetic profile of glimepiride was adequately described by the proposed PPK model. The CYP2C9 genotypes as covariate significantly (P < 0.001) influenced the apparent oral clearance (CL/F) of glimepiride. The estimated CL/F of glimepiride was higher (1.60-fold) in CYP2C9*1/*1 subjects than in CYP2C9*1/*3 subjects. CONCLUSIONS This study indicates that genetic polymorphisms of CYP2C9 influence the substantial interindividual variability in the disposition of glimepiride, and these polymorphisms may affect the clinical response to glimepiride therapy.
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Swen JJ, Wessels JAM, Krabben A, Assendelft WJJ, Guchelaar HJ. Effect of CYP2C9 polymorphisms on prescribed dose and time-to-stable dose of sulfonylureas in primary care patients with Type 2 diabetes mellitus. Pharmacogenomics 2011; 11:1517-23. [PMID: 21121772 DOI: 10.2217/pgs.10.121] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS Sulfonylureas are mainly metabolized by the enzyme CYP2C9. Two allelic variants, CYP2C9*2 and CYP2C9*3, result in decreased metabolic capacity and have been associated with elevated sulfonylurea serum levels. However, most of the available data originates from pharmacokinetic analyses performed in healthy individuals. In this study, the effect of CYP2C9*2 and CYP2C9*3 alleles on prescribed dose and time-to-stable dose of sulfonylureas was investigated. MATERIALS & METHODS A group of 207 incident sulfonylurea users treated in four university affiliated primary care centers were identified. The effect of the CYP2C9*2 and CYP2C9*3 alleles on prescribed dose and time-to-stable dose was then assessed. RESULTS No significant effects of the CYP2C9*2 and CYP2C9*3 alleles were found. However, a trend towards a lower stable glimepiride dose for carriers of the CYP2C9*3 allele was observed. CONCLUSION Genotyping for the CYP2C9*2 and CYP2C9*3 alleles currently appears to have no clinical implications for dosing of sulfonylureas in primary care patients with Type 2 diabetes mellitus.
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Affiliation(s)
- Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
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21
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Holstein A, Seeringer A, Kovacs P. Therapy with oral antidiabetic drugs: applied pharmacogenetics. ACTA ACUST UNITED AC 2011. [DOI: 10.1177/1474651410397583] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pharmacogenetics focuses on the relationship between individual gene variants and variable drug effects. The present brief review addresses the importance of pharmacogenetic factors for the efficacy and adverse effects of oral antidiabetic drugs in the therapy of type 2 diabetes mellitus. In particular, genetic polymorphisms of cytochrome P450 drug metabolizing enzymes, peroxisome proliferator-activated receptor- γ gene, TCF7L2 gene regulating insulin resistance and secretion and organic cation transporters or organic anion transporting polypeptides modify the individual response to drugs such as metformin, thiazolidinediones, sulphonylureas, meglitinides, and DPP4 inhibitors. However, apart from a complex variety of individual factors, genetic heterogeneity makes assessing the role of genetic factors in diabetes therapy for a single individual highly challenging. Continuing advances in pharmacogenetics will uncover further genetic variants that modify responses to diabetes medications and may offer targeted pharmacotherapy to the patient.
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Affiliation(s)
- Andreas Holstein
- First Department of Medicine, Clinic Lippe-Detmold, Detmold, Germany,
| | - Angela Seeringer
- Institute of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Ulm, Germany
| | - Peter Kovacs
- Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany
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22
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Holstein A, Hahn M, Patzer O, Seeringer A, Kovacs P, Stingl J. Impact of clinical factors and CYP2C9 variants for the risk of severe sulfonylurea-induced hypoglycemia. Eur J Clin Pharmacol 2011; 67:471-6. [PMID: 21213107 DOI: 10.1007/s00228-010-0976-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Accepted: 12/06/2010] [Indexed: 12/13/2022]
Abstract
AIMS The established risk factors for severe sulfonylurea-induced hypoglycemia (SH) include low hemoglobin (Hb)A(1c), advanced age, long duration of diabetes, multimorbidity, and polypharmacy. As the genetically polymorphic cytochrome P450 (CYP), enzyme CYP2C9 is mainly responsible for the hepatic metabolism of sulfonylureas (SUs), we hypothesized that the slow-metabolizer genotypes *2/*2, *2/*3, and *3/*3 might be overrepresented in type 2 diabetic patients with SH. METHODS In a prospective population-based case-control study, CYP2C9 allelic variants of 102 diabetic patients with SH were compared with a matched group of 101 SU-treated patients without a history of SH. The 203 Caucasian patients had been treated with the SUs glimepiride, glibenclamide, or gliquidone. SH was defined as a symptomatic event requiring treatment with intravenously administered glucose and was confirmed by a blood glucose measurement of <50 mg/dl (<2.8 mmol/l). As two control groups, we selected 337 Caucasian diabetic patients receiving antidiabetic drugs per os and 1,988 healthy Caucasian volunteers who had been genotyped earlier. RESULTS In the univariate analysis, only a low HbA(1c) value (p = 0.0004) was shown as a risk factor for SH. There was no overrepresentation of the CYP2C9 *2/*2, *2/*3, and *3/*3 variants in the SH group (2%) compared with the control group (5%). However, in the control group, patients with CYP2C9 genotypes, predicting slower metabolism of SU drugs, were treated with significantly lower doses (p = 0.027) than were extensive metabolizers, whereas in the patient group with severe hypoglycemia, the dose was the same for all genotype groups. CONCLUSIONS In the present cohort of 102 patients with SH, a low HbA(1c) value was related to the risk for SH. There was no overrepresentation observed of the CYP2C9 slow-metabolizer genotypes in the hypoglycemic patients group, but the drug exposure in the slow-metabolizer genotypes was estimated to be higher in hypoglycemic patients, which might partly have contributed to their risk for SH.
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Affiliation(s)
- Andreas Holstein
- First Department of Medicine, Klinikum Lippe-Detmold, Röntgenstr. 18, 32756 Detmold, Germany.
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Lee HW, Lim MS, Lee J, Jegal MY, Kim DW, Lee WK, Jang IJ, Shin JG, Yoon YR. Frequency of CYP2C9 variant alleles, including CYP2C9*13 in a Korean population and effect on glimepiride pharmacokinetics. J Clin Pharm Ther 2011; 37:105-11. [PMID: 21208246 DOI: 10.1111/j.1365-2710.2010.01238.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Cytochrome P450 (CYP) 2C9 is a clinically important enzyme involved in the metabolism of many drugs commonly used in humans. Of several allelic variants known to affect the catalytic activity of the CYP2C9 enzyme, the frequencies of the CYP2C9*3 and CYP2C9*13 alleles in the Korean population have been reported as 1·1% and 0·6%, respectively. Our objective was to re-evaluate the frequencies of CYP2C9 allelic variants in the Korean population, including the CYP2C9*13 allele by pyrosequencing, and to investigate the pharmacokinetics of glimepiride in relation to CYP2C9 genotypes, including CYP2C9*3/*3. METHODS 295 subjects were genotyped for CYP2C9*2 and CYP2C9*3 using the TaqMan procedure, and for CYP2C9*13 using pyrosequencing. These data were combined with our previously reported data to assess the CYP2C9 allele and genotype frequencies in 869 Korean subjects. Data from 24 of the 295 genotyped subjects (22 CYP2C9*1/*1 homozygotes, one CYP2C9*1/*3 heterozygote and one CYP2C9*3/*3 homozygote) who had participated in a bioequivalence study were analysed retrospectively to examine the effects of CYP2C9 genotype on glimepiride pharmacokinetics. RESULTS The frequencies of the CYP2C9*1/*3, *3/*3, and *1/*13 genotypes in the study population (n = 295) were 0·081 (n = 24), 0·010 (n = 3) and 0·003 (n = 1), respectively. In the 869 subjects from the combined studies, allele frequencies for CYP2C9*3 and CYP2C9*13 were 0·025 (95% CI: 0·018, 0·033) and 0·002 (95% CI: 0·000, 0·010), respectively. Relative to CYP2C9*1 homozygotes, the one CYP2C9*3 homozygous subject was found to have a higher AUC(0-∞) value (490% of the reference value) and a lower oral clearance rate (18% of the reference). WHAT IS NEW AND CONCLUSION This study is the first examination of CYP2C9*3 homozygotes in the Korean population. Our data on the one subject with this genotype suggest that CYP2C9*3/*3 momozygotes have lower clearance of glimepiride and are exposed to higher levels of the drug than wild-type homozygotes. Although we identified a subject with the CYP2C9*13 allele using a new pyrosequencing assay, we were unfortunately unable to investigate its effects on glimepiride pharmacokinetics.
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Affiliation(s)
- H W Lee
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Korea
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Shao H, Ren XM, Liu NF, Chen GM, Li WL, Zhai ZH, Wang DW. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. J Clin Pharm Ther 2010; 35:351-60. [PMID: 20831536 DOI: 10.1111/j.1365-2710.2009.01134.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND OBJECTIVE CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. METHODS Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography-tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose. RESULTS AND DISCUSSION There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC(0-∞) and C(max) in group C were significantly higher [83.94 ± 40.41 vs. 16.39 ± 5.10 μg·h/mL (P = 0.000) and 1.50 ± 0.85 vs. 0.45 ± 0.18 μg/mL (P = 0.000)], and the oral clearance was significantly lower [1.17 ± 0.63 vs. 5.38 ± 1.86 L/h (P = 0.000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33.47 ± 12.39 vs. 19.34 ± 10.45 h), but the difference was not significant (P = 0.052). The increase in serum glucose level at 11 h after dosing (ΔC(glu11)) in group C was significantly higher than that of group A (-1.08 ± 0.42 vs. 0.22 ± 1.01 mmol/L, P = 0.022). The corresponding insulin levels showed no difference between the two groups. CONCLUSION CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.
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Affiliation(s)
- H Shao
- Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
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Gu N, Kim BH, Rhim H, Chung JY, Kim JR, Shin HS, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS. Comparison of the bioavailability and tolerability of fixed-dose combination glimepiride/metformin 2/500-mg tablets versus separate tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy Korean volunteers. Clin Ther 2010; 32:1408-18. [DOI: 10.1016/j.clinthera.2010.07.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2010] [Indexed: 10/19/2022]
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Ragia G, Petridis I, Tavridou A, Christakidis D, Manolopoulos VG. Presence ofCYP2C9*3allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics 2009; 10:1781-7. [DOI: 10.2217/pgs.09.96] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41:89-295. [PMID: 19514967 DOI: 10.1080/03602530902843483] [Citation(s) in RCA: 541] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.
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Affiliation(s)
- Shu-Feng Zhou
- School of Health Sciences, RMIT University, Bundoora, Victoria, Australia.
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Maekawa K, Harakawa N, Sugiyama E, Tohkin M, Kim SR, Kaniwa N, Katori N, Hasegawa R, Yasuda K, Kamide K, Miyata T, Saito Y, Sawada JI. Substrate-dependent functional alterations of seven CYP2C9 variants found in Japanese subjects. Drug Metab Dispos 2009; 37:1895-903. [PMID: 19541829 DOI: 10.1124/dmd.109.027003] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
CYP2C9 is a polymorphic enzyme that metabolizes a number of clinically important drugs. In this study, catalytic activities of seven alleles found in Japanese individuals, CYP2C9*3 (I359L), *13 (L90P), *26 (T130R), *28 (Q214L), *30 (A477T), *33 (R132Q), and *34 (R335Q), were assessed using three substrates (diclofenac, losartan, and glimepiride). When expressed in a baculovirus-insect cell system, the holo and total (apo and holo) CYP2C9 protein expression levels were similar among the wild type (CYP2C9.1) and six variants except for CYP2C9.13. A large part of CYP2C9.13 was present in the apo form P420. Compared with CYP2C9.1, all variants except for CYP2C9.34 exhibited substrate-dependent changes in K(m), V(max), and intrinsic clearance (V(max)/K(m)). For diclofenac 4'-hydroxylation, the intrinsic clearance was decreased markedly (by >80%) in CYP2C9.13, CYP2C9.30, and CYP2C9.33 and variably (63-76%) in CYP2C9.3, CYP2C9.26, and CYP2C9.28 due to increased K(m) and/or decreased V(max) values. For losartan oxidation, CYP2C9.13 and CYP2C9.28 showed 2.5- and 1.8-fold higher K(m) values, respectively, and all variants except for CYP2C9.34 showed >77% lower V(max) and intrinsic clearance values. For glimepiride hydroxylation, the K(m) of CYP2C9.13 was increased 7-fold, and the V(max) values of all variants significantly decreased, resulting in reductions in the intrinsic clearance by >80% in CYP2C9.3, CYP2C9.13, CYP2C9.26, and CYP2C9.33 and by 56 to 75% in CYP2C9.28 and CYP2C9.30. These findings suggest the necessity for careful administration of losartan and glimepiride to patients bearing these six alleles.
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Affiliation(s)
- Keiko Maekawa
- Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
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Zhou SF, Zhou ZW, Huang M. Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology 2009; 278:165-88. [PMID: 19715737 DOI: 10.1016/j.tox.2009.08.013] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2009] [Revised: 08/18/2009] [Accepted: 08/21/2009] [Indexed: 12/19/2022]
Abstract
Human cytochrome P450 2C9 (CYP2C9) accounts for ∼20% of hepatic total CYP content and metabolizes ~15% clinical drugs such as phenytoin, S-warfarin, tolbutamide, losartan, and many nonsteroidal anti-inflammatory agents (NSAIDs). CYP2C9 is highly polymorphic, with at least 33 variants of CYP2C9 (*1B through *34) being identified so far. CYP2C9*2 is frequent among Caucasians with ~1% of the population being homozygous carriers and 22% are heterozygous. The corresponding figures for the CYP2C9*3 allele are 0.4% and 15%, respectively. There are a number of clinical studies addressing the impact of CYP2C9 polymorphisms on the clearance and/or therapeutic response of therapeutic drugs. These studies have highlighted the importance of the CYP2C9*2 and *3 alleles as a determining factor for drug clearance and drug response. The CYP2C9 polymorphisms are relevant for the efficacy and adverse effects of numerous NSAIDs, sulfonylurea antidiabetic drugs and, most critically, oral anticoagulants belonging to the class of vitamin K epoxide reductase inhibitors. Warfarin has served as a practical example of how pharmacogenetics can be utilized to achieve maximum efficacy and minimum toxicity. For many of these drugs, a clear gene-dose and gene-effect relationship has been observed in patients. In this regard, CYP2C9 alleles can be considered as a useful biomarker in monitoring drug response and adverse effects. Genetic testing of CYP2C9 is expected to play a role in predicting drug clearance and conducting individualized pharmacotherapy. However, prospective clinical studies with large samples are warranted to establish gene-dose and gene-effect relationships for CYP2C9 and its substrate drugs.
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Affiliation(s)
- Shu-Feng Zhou
- School of Health Sciences, RMIT University, Victoria 3083, Australia.
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Abstract
Genetic variation can impact on efficacy and risk of adverse events to commonly used oral agents in -diabetes. Metformin is not metabolized and its mechanism of action remains debated; however, several cation transporters have been identified. Variation in these pharmacokinetic genes might influence metformin response. Conversely, although the cytochrome P450 system has been implicated in sulfonylurea response in some small studies, to date variants affecting pharmacodynamics, including those in ABCC8 (SUR1) and TCF7L2, are the most promising. For thiazolidinedione response, variants in PPARG or ADIPOQ (adiponectin) have been variably associated with response. With increasing well-phenotyped cohorts and new methods, including genome-wide association studies, the next few years offer great hope to use pharmacogenetics to unravel drug and disease mechanisms, as well as the possibility to individualize therapy by genotype.
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Affiliation(s)
- Ewan R Pearson
- Biomedical Research Institute, Ninewells Hospital and Medical School, Ninewells Avenue, Dundee, DD1 9SY, UK.
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Chang TK. Drug-Metabolizing Enzymes. HANDBOOK OF DRUG-NUTRIENT INTERACTIONS 2009:85-117. [DOI: 10.1007/978-1-60327-362-6_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication. A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs. Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides. Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers. Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.
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Becker ML, Visser LE, Trienekens PH, Hofman A, van Schaik RHN, Stricker BHC. Cytochrome P450 2C9 *2 and *3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus. Clin Pharmacol Ther 2007; 83:288-92. [PMID: 17597710 DOI: 10.1038/sj.clpt.6100273] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Sulfonylurea hypoglycemics are mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme. The CYP2C9*2 and *3 polymorphisms encode proteins with less enzymatic activity and are correlated with elevated serum levels of sulfonylurea, as demonstrated in healthy volunteers. In this study, the effect of these variants is described for patients with diabetes mellitus treated with sulfonylurea. Associations between CYP2C9 polymorphisms, prescribed doses of sulfonylurea, and change in glucose levels after the start of sulfonylurea therapy were assessed in all patients with incident diabetes mellitus starting on sulfonylurea therapy in the Rotterdam Study, a population-based cohort study of 7,983 elderly people. In CYP2C9*3 allele carriers using tolbutamide, the prescribed dose was lower compared to patients with the wild-type CYP2C9 genotype. No differences in the prescribed dose were found in tolbutamide users with the CYP2C9*1/*2 or CYP2C9*2/*2 genotype compared to wild-type patients or in patients using other sulfonylurea. In CYP2C9*3 allele carriers, the mean decrease in fasting serum glucose levels after the start of tolbutamide therapy was larger than in patients with the wild-type genotype, although not statistically significant. Patients with diabetes mellitus who are carriers of a CYP2C9*3 allele require lower doses of tolbutamide to regulate their serum glucose levels compared to patients with the wild-type genotype.
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Affiliation(s)
- M L Becker
- Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands
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Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58:521-90. [PMID: 16968950 DOI: 10.1124/pr.58.3.6] [Citation(s) in RCA: 235] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
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Affiliation(s)
- Sharon J Gardiner
- Department of Medicine, Christchurch School of Medicine, Private Bag 4345, Christchurch, New Zealand.
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Kirchheiner J, Roots I, Goldammer M, Rosenkranz B, Brockmöller J. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet 2006; 44:1209-25. [PMID: 16372821 DOI: 10.2165/00003088-200544120-00002] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Type 2 diabetes mellitus affects up to 8% of the adult population in Western countries. Treatment of this disease with oral antidiabetic drugs is characterised by considerable interindividual variability in pharmacokinetics, clinical efficacy and adverse effects. Genetic factors are known to contribute to individual differences in bioavailability, drug transport, metabolism and drug action. Only scarce data exist on the clinical implications of this genetic variability on adverse drug effects or clinical outcomes in patients taking oral antidiabetics. The polymorphic enzyme cytochrome P450 (CYP) 2C9 is the main enzyme catalysing the biotransformation of sulphonylureas. Total oral clearance of all studied sulphonylureas (tolbutamide, glibenclamide [glyburide], glimepiride, glipizide) was only about 20% in persons with the CYP2C9*3/*3 genotype compared with carriers of the wild-type genotype CYP2C9*1/*1, and clearance in the heterozygous carriers was between 50% and 80% of that of the wild-type genotypes. For reasons not completely known, the resulting differences in drug effects were much less pronounced. Nevertheless, CYP2C9 genotype-based dose adjustments may reduce the incidence of adverse effects. The magnitude of how doses might be adjusted can be derived from pharmacokinetic studies. The meglitinide-class drug nateglinide is metabolised by CYP2C9. According to the pharmacokinetic data, moderate dose adjustments based on CYP2C9 genotypes may help in reducing interindividual variability in the antihyperglycaemic effects of nateglinide. Repaglinide is metabolised by CYP2C8 and, according to clinical studies, CYP2C8*3 carriers had higher clearance than carriers of the wild-type genotypes; however, this was not consistent with in vitro data and therefore further studies are needed. CYP2C8*3 is closely linked with CYP2C9*2. CYP2C8 and CYP3A4 are the main enzymes catalysing biotransformation of the thiazolidinediones troglitazone and pioglitazone, whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. The biguanide metformin is not significantly metabolised but polymorphisms in the organic cation transporter (OCT) 1 and OCT2 may determine its pharmacokinetic variability. In conclusion, pharmacogenetic variability plays an important role in the pharmacokinetics of oral antidiabetic drugs; however, to date, the impact of this variability on clinical outcomes in patients is mostly unknown and prospective studies on the medical benefit of CYP genotyping are required.
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Affiliation(s)
- Julia Kirchheiner
- Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University, Berlin, Germany.
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Jovanović D, Stojsić D, Zlatković M, Jović-Stosić J, Jovanović M. Bioequivalence assessment of the two brands of glimepiride tablets. VOJNOSANIT PREGL 2006; 63:1015-20. [PMID: 17252706 DOI: 10.2298/vsp0612015j] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background/Aim. Glimepiride, as an antidiabetic from the group of sulfonylurea, is administered perorally in the treatment of diabetes mellitus. The aim of this study was to compare pharmacokinetic profiles and relative bioavailabilities of the two oral formulations of glimepiride, generic and innovator tablets, after a single dose of the active drug. Methods. An oral dose of 6 mg glimepiride was given under fasting conditions to 24 healthy volunteers. A one-week washout period was applied between the two consecutive periods. The serum samples obtained before dosing, and at various time points up to 48 hours, were analyzed for glimepiride concentration using the validated highperformance liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters representing early (maximal concentration, time to reach maximal concentration) and total exposure (area under the curve from the time 0 to the infinite time) to glimepiride were obtained and further analyzed using the multifactorial analysis of variance and the non-parametric Wilcoxon signed ranks test. Comparison of the secondary kinetic variables was only descriptive. Results. The point estimates of the ratios of geometric means (test/reference) of maximal concentrations and areas under the curve were 1.046 (90% confidence interval: 0.906?1.208) and 1.022 (90% confidence interval: 0.856?1.220), respectively, while the median values of times to reach maximal concentration, at 5% level of significance, did not differ significantly. Both formulations were well tolerated. Transient mild hypoglycaemia, which had been noted in 6 participants, resolved spontaneously within 30?60 minutes. Conclusion. Since all the parametric 90% confidence intervals for the log-transformed main variables of glimepiride were within the 0.80 and 1.25 interval, accepted as the definition of bioequivalence, and the differences in times to reach maximal concentration also did not reach statistical significance, studied tablets were considered bioequivalent.
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Affiliation(s)
- Dusan Jovanović
- Military Medical Academy, National Poison Control Centre, Belgrade, Serbia.
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