Abstract

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 K_M for diclofenac metabolism rose from 4.5 ± 0.5 to 21 ± 6 μM, andV_max 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 apparentK_i 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 K_iof 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 aK_i of 12.8 ± 1.8 μM, similar to the observed K_M 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.