SELECTIVE BIOTRANSFORMATION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE INHIBITOR SAQUINAVIR BY HUMAN SMALL-INTESTINAL CYTOCHROME P4503A4 - POTENTIAL CONTRIBUTION TO HIGH FIRST-PASS METABOLISM

Saquinavir is a HIV1 protease inhibitor used in the treatment of patie nts with acquired immunodeficiency syndrome, but its use is limited by low oral bioavailability. The potential of human intestinal tissue to metabolize saquinavir was assessed in 17 different human small-intest inal microsomal preparations. Saquinavir was metabolized by human smal l-intestinal microsomes to numerous mono- and dihydroxylated species w ith K-M values of 0.3-0.5 mu M. The major metabolites M-2 and M-7 were single hydroxylations on the octahydro-2-(1H)-isoquinolinyl and (1,1- dimethylethyl)amino groups, respectively. Ketoconazole and troleandomy cin, selective inhibitors of cytochrome P4503A4 (CYP3A4), were potent inhibitors for all oxidative metabolites of saquinavir. The cytochrome P450-selective inhibitors furafylline, fluvoxamine, sulfaphenazole, m ephenytoin, quinidine, and chlorzoxazone had little inhibitory effect. All saquinavir metabolites were highly correlated with testosterone 6 beta-hydroxylation and with each other. Human hepatic microsomes and recombinant CYP3A4 oxidized saquinavir to the same metabolic profile o bserved with human small-intestinal microsomes. Indinavir, a potent HI V protease inhibitor and a substrate for human hepatic CYP3A4, was a c omparatively poor substrate for human intestinal microsomes and inhibi ted the oxidative metabolism of saquinavir to all metabolites with a K -l of 0.2 mu M. In addition, saquinavir inhibited the human, small-int estinal, microsomal CYP3A4-dependent detoxication pathway of terfenadi ne to its alcohol metabolite with a K-l value of 0.7 mu M. These data indicate that saquinavir is metabolized by human intestinal CYP3A4, th at this metabolism may contribute to its poor oral bioavailability, an d that combination therapy with indinavir or other protease inhibitors may attenuate its low relative bioavailability.