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 1998-07, Vol.87 (7), p.803-807
Main Authors: Decker, Caroline J., Laitinen, Leena M., Bridson, Gary W., Raybuck, Scott A., Tung, Roger D., Chaturvedi, Pravin R.
Format: Article
Language:English
Subjects:
Anti-HIV Agents - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
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
Medical sciences
Microsomes, Liver - enzymology
Microsomes, Liver - metabolism
Mixed Function Oxygenases - antagonists & inhibitors
Mixed Function Oxygenases - metabolism
Pharmacology. Drug treatments
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 K value for amprenavir-mediated inhibition of testosterone hydroxylation in human liver microsomes was found to be approximately 0.5 μM. 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
1520-6017
DOI:10.1021/js980029p