Abstract
The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is directly conjugated by the UDP-glucuronosyltransferase (UGT) pathway to form EFV-N-glucuronide (EFV-G), but the enzyme(s) involved has not yet been identified. The glucuronidation of EFV was screened with UGT1A and UGT2B enzymes expressed in a heterologous system, and UGT2B7 was shown to be the only reactive enzyme. The apparent Km value of UGT2B7 (21 μM) is similar to the value observed for human liver microsomes (24 μM), whereas the variant allozyme UGT2B7*2 (Tyr268) displayed similar kinetic parameters. Because 3′-azido-3′-deoxythymidine (AZT), one of the most current nucleotide reverse transcriptase inhibitors prescribed in combination with EFV, is also conjugated by UGT2B7, the potential metabolic interaction between EFV and AZT has been studied using human liver microsomes. Glucuronidation of both drugs was inhibited by one another, in a concentration-dependent manner. At Km values (25 and 1000 μM for EFV and AZT, respectively), EFV inhibited AZT glucuronidation by 47%, whereas AZT inhibited EFV glucuronidation by 23%. With a Ki value of 17 μM for AZT-glucuronide formation, EFV appears to be one of the most selective and potent competitive inhibitor of AZT glucuronidation in vitro. Moreover, assuming that concentrations of EFV achieved in plasma (Cmax = 12.9 μM) are in a range similar to its Ki value, it was estimated that EFV could produce a theoretical 43% inhibition of AZT glucuronidation in vivo. We conclude that UGT2B7 has a major role in EFV glucuronidation and that EFV could potentially interfere with the hepatic glucuronidation of AZT.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of Allergy and Infectious Diseases Extramural Activities [Grant AI36219] (to the Center for AIDS Research, Developmental Awards, Case/University Hospitals of Cleveland, Cleveland, OH) (to R.K.M. and C.G.); A.-S.B. was supported by a Canada Graduate Scholarship Doctoral Research Award from the Canada Institutes of Health Research; and C.G. is the holder of a Canada Research Chair in Pharmacogenomics.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027706.
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ABBREVIATIONS: EFV, efavirenz; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; AZT, zidovudine; UGT, UDP-glucuronosyltransferase; EFV-G, EFV-N-glucuronide; AZT-G, AZT-glucuronide; HLM, human liver microsomes.
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↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
- Accepted May 28, 2009.
- Received March 26, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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