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

• Published in: European journal of clinical pharmacology Vol. 56; no. 3; pp. 259 - 261
• Main Authors: VON MOLTKE, L. L, DUROL, A. L. B, DUAN, S. X, GREENBLATT, D. J
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.06.2000; Berlin Springer Nature B.V
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Carbamates; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Humans; Hydroxylation; Ketoconazole - pharmacology; Medical sciences; Oxidoreductases, N-Demethylating - antagonists & inhibitors; Pharmacology. Drug treatments; Protease inhibitors; Ritonavir - pharmacology; Sulfonamides - pharmacology; Triazolam - metabolism; Human; Ketoconazole; Isozyme; Ritonavir; Cytochrome P450; Liver; Enzyme inhibitor; Microsome; Metabolism; In vitro; Antiviral; Amprenavir; Comparative study; Protease inhibitor
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s002280000125

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