TY - JOUR T1 - Interaction of Delavirdine with Human Liver Microsomal Cytochrome P450: Inhibition of CYP2C9, CYP2C19, and CYP2D6 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 41 LP - 47 VL - 29 IS - 1 AU - Richard L. Voorman AU - N. Ann Payne AU - Larry C. Wienkers AU - Michael J. Hauer AU - Phillip E. Sanders Y1 - 2001/01/01 UR - http://dmd.aspetjournals.org/content/29/1/41.abstract N2 - Delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is metabolized primarily through desalkylation catalyzed by CYP3A4 and CYP2D6 and by pyridine hydroxylation catalyzed by CYP3A4. It is also an irreversible inhibitor of CYP3A4. The interaction of delavirdine with CYP2C9 was examined with pooled human liver microsomes using diclofenac 4′-hydroxylation as a reporter of CYP2C9 catalytic activity. As delavirdine concentration was increased from 0 to 100 μM, the KM for diclofenac metabolism rose from 4.5 ± 0.5 to 21 ± 6 μM, andVmax declined from 4.2 ± 0.1 to 0.54 ± 0.08 nmol/min/mg of protein, characteristic of mixed-type inhibition. Nonlinear regression analysis revealed an apparentKi of 2.6 ± 0.4 μM. There was no evidence for bioactivation as prerequisite to inhibition of CYP2C9. Desalkyl delavirdine, the major circulating metabolite of delavirdine, had no apparent effect on microsomal CYP2C9 activity at concentrations up to 20 μM. Several analogs of delavirdine showed similar inhibition of CYP2C9. Delavirdine significantly inhibited cDNA-expressed CYP2C19-catalyzed (S)-mephenytoin 4′-hydroxylation in a noncompetitive manner, with an apparent Kiof 24 ± 3 μM. Delavirdine at concentrations up to 100 μM did not inhibit the activity of CYP1A2 or -2E1. Delavirdine competitively inhibited recombinant CYP2D6 activity with aKi of 12.8 ± 1.8 μM, similar to the observed KM for delavirdine desalkylation. These results, along with previously reported experiments, indicate that delavirdine can partially inhibit CYP2C9, -2C19, -2D6, and -3A4, although the degree of inhibition in vivo would be subject to a variety of additional factors. The American Society for Pharmacology and Experimental Therapeutics ER -