METABOLISM OF AMPRENAVIR IN LIVER-MICROSOMES - ROLE OF CYP3A4 INHIBITION FOR DRUG-INTERACTIONS

Amprenavir (141W94, VX-478, KVX-478) is metabolized primarily by CYP3A 4 (cytochrome P450 3A4) in recombinant systems and human liver microso mes (HLM). The effects of ketoconazole, terfenadine, astemizole, rifam picin, methadone, and rifabutin upon amprenavir metabolism were examin ed 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, saquin avir, ritonavir, and nelfinavir, were included in incubations containi ng amprenavir to examine the interactions of HIV protease inhibitors i n vitro. The order of amprenavir metabolism inhibition in human liver microsomes was observed to be: ritonavir > indinavir > nelfinavir > sa quinavir. The K-i value for amprenavir-mediated inhibition of testoste rone hydroxylation in human liver microsomes was found to be approxima tely 0.5 mu M. Studies suggest that amprenavir inhibits CYP3A4 to a gr eater extent than saquinavir, and to a much lesser extent than ritonav ir. Amprenavir, nelfinavir, and indinavir appear to inhibit CYP3A4 to a moderate extent, suggesting a selected number of coadministration re strictions.