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

Objective: Biotransformation of triazolam to its a-hydroxy and 4-hydroxy metabolites by human liver microsomes in vitro was used as an index of human cytochrome P-450 3A (CYP3A) activity. Results: The reaction was strongly inhibited by co-incubation with the viral protease inhibitors ritonavir (IC50 = 0.14 mu M) and amprenavir (IC50 = 2.5-2.9 mu M), and by the azole derivative ketoconazole (IC50 = 0.07 mu M) Pre-incubation of microsomes with ritonavir or amprenavir increased inhibitory potency (IC50 reduced to 0.07 mu M and 1.4 mu M, respectively). This was not the case with ketoconazole. Conclusions: Thus, ritonavir and amprenavir are highly potent mechanism-based inhibitors of human CYP3A isoforms.