Publication: The glucuronidation of R- and S-lorazepam: Human liver microsomal kinetics, UDP-glucuronosyltransferase enzyme selectivity, and inhibition by drugs
Issued Date
2013-06-01
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ISSN
1521009X
00909556
00909556
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2-s2.0-84878218091
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Mahidol University
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SCOPUS
Bibliographic Citation
Drug Metabolism and Disposition. Vol.41, No.6 (2013), 1273-1284
Suggested Citation
Verawan Uchaipichat, Chuthamanee Suthisisang, John O. Miners The glucuronidation of R- and S-lorazepam: Human liver microsomal kinetics, UDP-glucuronosyltransferase enzyme selectivity, and inhibition by drugs. Drug Metabolism and Disposition. Vol.41, No.6 (2013), 1273-1284. doi:10.1124/dmd.113.051656 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/32738
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Title
The glucuronidation of R- and S-lorazepam: Human liver microsomal kinetics, UDP-glucuronosyltransferase enzyme selectivity, and inhibition by drugs
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Abstract
The widely used hypnosedative-anxiolytic agent R,S-lorazepam is cleared predominantly by conjugation with glucuronic acid in humans, but the enantioselective glucuronidation of lorazepam has received little attention. The present study characterized the kinetics of the separate R and S enantiomers of lorazepam by human liver microsomes (HLMs) and by a panel of recombinant human UDP-glucuronosyltransferase (UGT) enzymes. Respective mean Km and Vmax values for R- and S-lorazepam glucuronidation by HLM were 29 ± 8.9 and 36 ± 10 μM, and 7.4 ± 1.9 and 10 ± 3.8 pmol/min × mg. Microsomal intrinsic clearances were not significantly different, suggesting the in vivo clearances of R- and S-lorazepam are likely to be similar. Both R- and S-lorazepam were glucuronidated by UGT2B4, 2B7, and 2B15, whereas R-lorazepam was additionally metabolized by the extrahepatic enzymes UGT1A7 and 1A10. Based on in vitro clearances and consideration of available in vivo and in vitro data, UGT2B15 is likely to play an important role in the glucuronidation of R- and S-lorazepam. However, the possible contribution of other enzymes and the low activities observed in vitro indicate that the lorazepam enantiomers are of limited use as substrate probes for UGT2B15. To identify potential drug-drug interactions, codeine, fluconazole, ketamine, ketoconazole, methadone, morphine, valproic acid, and zidovudine were screened as inhibitors of R- and S-lorazepam glucuronidation by HLM. In vitro-in vivo extrapolation suggested that, of these drugs, only ketoconazole had the potential to inhibit lorazepam clearance to a clinically significant extent. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.