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      Metabolic Interaction Potential between Clopidogrel and Sulfonylurea Antidiabetic Agents: Effects on Clopidogrel Bioactivation

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          Abstract

          Background: Patients with diabetes have increased rates of cardiovascular events, and concomitant use of antidiabetic agents and clopidogrel may increase the risk for drug interactions. This study was undertaken to investigate the interaction potential between sulfonylurea drugs and clopidogrel, with an emphasis on key steps in the clopidogrel bioactivation processes. Methods: Inhibition of clopidogrel metabolism by sulfonylureas was evaluated by monitoring the formation of clopidogrel carboxylic acid and 2-oxo-clopidogrel in human liver microsomes (HLM), human intestinal microsomes and recombinant human enzymes. CYP2C9-based interaction was investigated for both 2-oxo-clopidogrel and glimepiride using HLM and the recombinant CYP2C9 system. Results: For the formation of clopidogrel carboxylic acid (the deactivation step) and 2-oxo-clopidogrel (the first step of bioactivation) in human microsomes, the inhibition potency of the 3 sulfonylurea drugs tested followed the order of glimepiride > glipizide > gliclazide. For the metabolism of 2-oxo-clopidogrel (the second step of bioactivation), glimepiride demonstrated a relatively strong inhibition against CYP2C9 activity (IC 50 12.7 μmol/l). In addition, 2-oxo-clopidogrel displayed a moderate inhibitory effect toward the CYP2C9-mediated metabolism of glimepiride. Conclusion: The moderate inhibition observed for clopidogrel bioactivation may not present a significant risk for drug-drug interactions between sulfonylureas and clopidogrel. While these findings bode well for multidrug therapies involving sulfonylureas and clopidogrel, clinical investigations are needed to define the clinical risk and benefit for combining these agents for the management of cardiovascular events in diabetic patients.

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          Most cited references 18

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          Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update.

          Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype-directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).
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            Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.

            The aim of the current study is to identify the human cytochrome P450 (P450) isoforms involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. In the in vitro experiments using cDNA-expressed human P450 isoforms, clopidogrel was metabolized to 2-oxo-clopidogrel, the immediate precursor of its pharmacologically active metabolite. CYP1A2, CYP2B6, and CYP2C19 catalyzed this reaction. In the same system using 2-oxo-clopidogrel as the substrate, detection of the active metabolite of clopidogrel required the addition of glutathione to the system. CYP2B6, CYP2C9, CYP2C19, and CYP3A4 contributed to the production of the active metabolite. Secondly, the contribution of each P450 involved in both oxidative steps was estimated by using enzyme kinetic parameters. The contribution of CYP1A2, CYP2B6, and CYP2C19 to the formation of 2-oxo-clopidogrel was 35.8, 19.4, and 44.9%, respectively. The contribution of CYP2B6, CYP2C9, CYP2C19, and CYP3A4 to the formation of the active metabolite was 32.9, 6.76, 20.6, and 39.8%, respectively. In the inhibition studies with antibodies and selective chemical inhibitors to P450s, the outcomes obtained by inhibition studies were consistent with the results of P450 contributions in each oxidative step. These studies showed that CYP2C19 contributed substantially to both oxidative steps required in the formation of clopidogrel active metabolite and that CYP3A4 contributed substantially to the second oxidative step. These results help explain the role of genetic polymorphism of CYP2C19 and also the effect of potent CYP3A inhibitors on the pharmacokinetics and pharmacodynamics of clopidogrel in humans and on clinical outcomes.
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              Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.

              Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y(12) adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC(0-24); P = 0.004) and maximal plasma concentration (C(max); P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC(0-24) (P = 0.043), lower C(max) (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.
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                Author and article information

                Journal
                PHA
                Pharmacology
                10.1159/issn.0031-7012
                Pharmacology
                Pharmacology
                S. Karger AG (Basel, Switzerland karger@ 123456karger.com http://www.karger.com )
                0031-7012
                1423-0313
                January 2016
                17 November 2015
                : 97
                : 1-2
                : 18-24
                Affiliations
                aDepartment of Pharmacy, Zhongda Hospital, Southeast University, Nanjing, and bCollege of Pharmaceutical Sciences, Soochow University, Suzhou, China
                Article
                PHA20160971-2018 Pharmacology 2016;97:18-24
                10.1159/000441230
                26569597
                © 2015 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 2, References: 19, Pages: 7
                Categories
                Original Paper

                Medicine, General social science

                Sulfonylurea, Clopidogrel, Bioactivation, Inhibition, Drug interaction

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