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

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 HL...

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Bibliographic Details
Published in:	Journal of pharmaceutical sciences Vol. 87; no. 7; p. 803
Main Authors:	Decker, C J, Laitinen, L M, Bridson, G W, Raybuck, S A, Tung, R D, Chaturvedi, P R
Format:	Journal Article
Language:	English
Published:	United States 01-07-1998
Subjects:	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 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
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Summary:	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.
ISSN:	0022-3549
DOI:	10.1021/js980029p