Glucuronidation of the Antiretroviral Drug Efavirenz by UGT2B7 and an in Vitro Investigation of Drug-Drug Interaction with Zidovudine

• DOI: 10.1124/dmd.109.027706
• Publication Date: 2009-06-02T00:54:38Z
• Authors: Anne-Sophie Bélanger; Patrick Caron; Mario Harvey; Peter A. Zimmerman; Rajeev K. Mehlotra; Chantal Guillemette
• Keywords: UGT2B7; Efavirenz; Glucuronide; Reverse-transcriptase inhibitor

The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is directly conjugated by the UDP-glucuronosyltransferase (UGT) pathway to form EFV-<i>N</i>-glucuronide (EFV-G), but enzyme(s) involved has not yet been identified. glucuronidation of EFV was screened with UGT1A and UGT2B enzymes expressed in a heterologous system, UGT2B7 shown be only reactive enzyme. apparent <i>K</i>_m value (21 μM) similar observed for human liver microsomes (24 μM), whereas variant allozyme UGT2B7*2 (Tyr²⁶⁸) displayed kinetic parameters. Because 3′-azido-3′-deoxythymidine (AZT), one most current nucleotide inhibitors prescribed combination EFV, also UGT2B7, potential metabolic interaction between AZT studied using microsomes. Glucuronidation both drugs inhibited another, concentration-dependent manner. At values (25 1000 μM AZT, respectively), 47%, 23%. With <i>K</i>_i 17 AZT-glucuronide formation, appears selective potent competitive vitro. Moreover, assuming that concentrations achieved plasma (<i>C</i>_max = 12.9 are range its value, it estimated could produce theoretical 43% inhibition vivo. We conclude major role potentially interfere hepatic AZT.