Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6

Drug Metab Dispos. 2001 Jan;29(1):41-7.


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 microM, the K(M) for diclofenac metabolism rose from 4.5+/-0.5 to 21+/-6 microM, and V(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 apparent K(i) of 2.6+/-0.4 microM. 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 microM. 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(i) of 24+/-3 microM. Delavirdine at concentrations up to 100 microM did not inhibit the activity of CYP1A2 or -2E1. Delavirdine competitively inhibited recombinant CYP2D6 activity with a K(i) of 12.8+/-1.8 microM, 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.

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP2D6 Inhibitors*
  • Cytochrome P-450 Enzyme Inhibitors*
  • Delavirdine / pharmacology*
  • Diclofenac / pharmacokinetics
  • Humans
  • Hydroxylation
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Recombinant Proteins / antagonists & inhibitors
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / antagonists & inhibitors*


  • Anti-HIV Agents
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Recombinant Proteins
  • Reverse Transcriptase Inhibitors
  • Diclofenac
  • Delavirdine
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A2 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Steroid 16-alpha-Hydroxylase