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Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate

Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel acyl glucuronide (CAG) by uridine diphosphate‐glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean Vmax value of 120.9 pmol/min/mg protein, 3‐ to 12‐fold higher than that of the other rUGT isoforms tested. According to relative activity factor approach, the relative contribution of rUGT2B7 to CCA glucuronidation was estimated to be 58.6%, with the minor contributions (3%) from rUGT1A9. Moreover, the glucuronidation of CCA followed Michaelis‐Menten kinetics with a mean Km value of 372.9 μM and 296.4 μM for pooled HLMs and rUGT2B7, respectively, showing similar affinity for both. The formation of CAG was significantly inhibited by azidothymidine and gemfibrozil (well‐characterized UGT2B7 substrates) in a concentration‐dependent manner, or by fluconazole (a typical UGT2B7‐selective inhibitor) in a time‐dependent manner, for both HLMs and rUGT2B7, respectively. In addition, CCA inhibited azidothymidine glucuronidation (catalyzed almost exclusively by UGT2B7) by HLMs and rUGT2B7 in a concentration‐dependent manner, indicating that CCA is a substrate of UGT2B7. These results reveal that UGT2B7 is the major enzyme catalyzing clopidogrel glucuronidation in the human liver, and that there is the potential for drug‐drug interactions between clopidogrel and the other substrate drugs of UGT2B7.