Metabolism of Amprenavir in Liver Microsomes: Role of CYP3A4 Inhibition for Drug Interactions
- 1 July 1998
- journal article
- Published by American Geophysical Union (AGU) in Journal of Pharmaceutical Sciences
- Vol. 87 (7), 803-807
- https://doi.org/10.1021/js980029p
Abstract
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.Keywords
This publication has 4 references indexed in Scilit:
- Treatment with Indinavir, Zidovudine, and Lamivudine in Adults with Human Immunodeficiency Virus Infection and Prior Antiretroviral TherapyNew England Journal of Medicine, 1997
- Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavirBritish Journal of Clinical Pharmacology, 1997
- Protease Inhibitors in Patients with HIV DiseaseClinical Pharmacokinetics, 1997
- Weak Binding of VX-478 to Human Plasma Proteins and Implications for Anti-Human Immunodeficiency Virus TherapyThe Journal of Infectious Diseases, 1995