Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole

Eur J Clin Pharmacol. 2000 Jun;56(3):259-61. doi: 10.1007/s002280000125.


Objective: Biotransformation of triazolam to its alpha-hydroxy and 4-hydroxy metabolites by human liver microsomes in vitro was used as an index of human cytochrome P450 3A (CYP3A) activity.

Results: The reaction was strongly inhibited by co-incubation with the viral protease inhibitors ritonavir (IC50 = 0.14 microM) and amprenavir (IC50 = 2.5 2.9 microM), and by the azole derivative ketoconazole (IC50 = 0.07 microM). Pre-incubation of microsomes with ritonavir or amprenavir increased inhibitory potency (IC50 reduced to 0.07 microM and 1.4 microM, respectively). This was not the case with ketoconazole.

Conclusions: Thus, ritonavir and amprenavir are highly potent mechanism-based inhibitors of human CYP3A isoforms.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aryl Hydrocarbon Hydroxylases*
  • Carbamates
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Enzyme Inhibitors / pharmacology*
  • Furans
  • Humans
  • Hydroxylation
  • Ketoconazole / pharmacology*
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors*
  • Ritonavir / pharmacology*
  • Sulfonamides / pharmacology*
  • Triazolam / metabolism


  • Carbamates
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Furans
  • Sulfonamides
  • Triazolam
  • amprenavir
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Ritonavir
  • Ketoconazole