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Thursday 01 June 2000

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

By: von Moltke LL, Durol AL, Duan SX, Greenblatt DJ.

Eur J Clin Pharmacol 2000 Jun;56(3):259-61

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

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