Reactions 1680, p7 - 2 Dec 2017 Effect of clopidogrel glucuronidation enzyme deletion Metabolism of clopidogrel to clopidogrel acyl-β-D- glucuronide is impaired in carriers of a UDP- glucuronosyltransferase (UGT) gene deletion, according to study results reported in Drug Metabolism and Disposition, and "the findings may have implications with regard to drug-drug interactions caused by inactivation of CYP2C8 by clopidogrel acyl-β-D- glucuronide". Although some metabolism of the prodrug clopidogrel is via oxidation to the active metabolite, catalysed by several CYP isoforms, most metabolism is via sequential hydrolysis and conjugation reactions to clopidogrel carboxylic acid and clopidogrel acyl-β-D- glucuronide. Clopidogrel is an inhibitor of CYP2C19 and CYP2B6; the tendency to form reactive metabolites which irreversibly inactive CYP enzymes, especially CYP2C8, has also been observed for clopidogrel acyl-β- D-glucuronide. The in vitro study investigated the role of 13 UGTs in the formation of clopidogrel acyl-β-D-glucuronide. UGT1A1, UGT1A8, UGT1A10 and UGT2B10 were not associated with the formation of any detectable clopidogrel acyl-β-D-glucuronide, and the activity was low/negligible for UGT1A4, UGT1A6, UGT1A7 and UGT2B15. UGT2B17 and UGT2B7 had the highest activity, while UGT1A3, USG1A9, UGT1A10-H and UGT2B4 also had significant activity. The presence of the UGT2B17 inhibitor imatinib inhibited clopidogrel carboxylic acid glucuronidation in human intestine microsomes, while the presence of the UGT2B7 and UGT1A9 inhibitor mefenamic acid inhibited glucuronidation in human liver microsomes. The presence of gemfibrozil, or the nonselective UGT2B inhibitors aprepitant, fluconazole and ketamine, inhibited glucuronidation in both liver and intestine microsomes. UGT2B17 had the highest unbound intrinsic clearance in the intestine, while UGT2B7 had the highest unbound intrinsic liver microsomal clearance. The pharmacokinetics of clopidogrel carboxylic acid glucuronidation were investigated in 106 healthy volunteers who received clopidogrel. The presence of the UGT2B17*2 deletion allele was associated with altered clopidogrel pharmacokinetic parameters. Each allele prolonged the clopidogrel carboxylic acid t1 by /2 8.7% and the clopidogrel acyl-β-D-glucuronide t1 by /2 6.5%, and decreased the clopidogrel carboxylic acid to clopidogrel acyl-β-D-glucuronide plasma AUC ratio 0–4 by 10.1%. The UGT2B7*2 gene polymorphism did not have a significant effect on t1 or AUC values. /2 "The present study indicates that UGT2B7 is the main enzyme involved in clopidogrel carboxylic acid glucuronidation in the liver," note the authors, "while at least UGT2B4, and possibly also UGT1A9 and UGT2B17 play a smaller role. On the other hand, UGT2B17 has a major role in the intestinal metabolism of clopidogrel. Consequently, the formation of clopidogrel acyl-β-D- glucuronide is impaired in carriers of the UGT2B17 gene deletion". Kahma H, et al. Clopidogrel carboxylic acid glucuronidation is mediated mainly by UGT2B7, UGT2B4 and UGT2B17: Implications for pharmacogenetics and drug- drug interactions. Drug Metabolism and Disposition : 14 Nov 2017. Available from: URL: http://doi.org/10.1124/dmd.117.078162 803284986 0114-9954/17/1680-0001/$14.95 Adis © 2017 Springer International Publishing AG. All rights reserved Reactions 2 Dec 2017 No. 1680
Reactions Weekly – Springer Journals
Published: Dec 2, 2017
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