Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions

J Pharm Sci. 1998 Jul;87(7):803-7. doi: 10.1021/js980029p.


Amprenavir (141W94, VX-478, KVX-478) is metabolized primarily by CYP3A4 (cytochrome P450 3A4) in recombinant systems and human liver microsomes (HLM). The effects of ketoconazole, terfenadine, astemizole, rifampicin, methadone, and rifabutin upon amprenavir metabolism were examined in vitro using HLM. Ketoconazole, terfenadine, and astemizole were observed to inhibit amprenavir depletion, consistent with their known specificity for CYP3A4. The HIV protease inhibitors, indinavir, saquinavir, ritonavir, and nelfinavir, were included in incubations containing amprenavir to examine the interactions of HIV protease inhibitors in vitro. The order of amprenavir metabolism inhibition in human liver microsomes was observed to be: ritonavir > indinavir > nelfinavir > saquinavir. The Ki value for amprenavir-mediated inhibition of testosterone hydroxylation in human liver microsomes was found to be approximately 0.5 microM. Studies suggest that amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir. Amprenavir, nelfinavir, and indinavir appear to inhibit CYP3A4 to a moderate extent, suggesting a selected number of coadministration restrictions.

MeSH terms

  • Anti-HIV Agents / pharmacology
  • Carbamates
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Furans
  • HIV Protease Inhibitors / metabolism*
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism*
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism
  • Ritonavir / pharmacology
  • Saquinavir / pharmacology
  • Sulfonamides / metabolism*
  • Sulfonamides / pharmacology*


  • Anti-HIV Agents
  • Carbamates
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Furans
  • HIV Protease Inhibitors
  • Isoenzymes
  • Sulfonamides
  • amprenavir
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Saquinavir
  • Ritonavir