Received for publication March 27, 2009.
Revised May 27, 2009.
Accepted for publication May 28, 2009.

Glucuronidation of the antiretroviral drug efavirenz (EFV) by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine (AZT)

Abstract

The nonnucleoside 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 been identified yet. 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 K_m value of UGT2B7 (21 µM) is similar to the value observed for human liver microsomes (24 µM) while the variant allozyme UGT2B7*2 (Y²⁶⁸) displayed similar kinetic parameters. Since 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 K_m values (25 and 1000 µM for EFV and AZT, respectively), EFV inhibited AZT glucuronidation by 47%, while AZT inhibited EFV glucuronidation by 23%. With a K_i value of 17 µM for AZT-G 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 (C_max = 12.9 µM) are in a range similar to its K_i 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.

Key words: antivirals, drug-drug interactions, enzyme kinetics, genetic polymorphism, glucuronidation, phase II drug metabolism, UDP glucuronyltransferases