PT  - JOURNAL ARTICLE
AU  - Fitzsimmons, Michael E.
AU  - Collins, Jerry M.
TI  - Selective Biotransformation of the Human Immunodeficiency Virus Protease Inhibitor Saquinavir by Human Small-Intestinal Cytochrome P4503A4
DP  - 1997 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 256--266
VI  - 25
IP  - 2
4099  - http://dmd.aspetjournals.org/content/25/2/256.short
4100  - http://dmd.aspetjournals.org/content/25/2/256.full
SO  - Drug Metab Dispos1997 Feb 01; 25
AB  - Saquinavir is a HIV1 protease inhibitor used in the treatment of patients 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-intestinal microsomal preparations. Saquinavir was metabolized by human small-intestinal microsomes to numerous mono- and dihydroxylated species with KM values of 0.3–0.5 μM. 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 troleandomycin, selective inhibitors of cytochrome P4503A4 (CYP3A4), were potent inhibitors for all oxidative metabolites of saquinavir. The cytochrome P450-selective inhibitors furafylline, fluvoxamine, sulfaphenazole, mephenytoin, quinidine, and chlorzoxazone had little inhibitory effect. All saquinavir metabolites were highly correlated with testosterone 6β-hydroxylation and with each other. Human hepatic microsomes and recombinant CYP3A4 oxidized saquinavir to the same metabolic profile observed with human small-intestinal microsomes. Indinavir, a potent HIV protease inhibitor and a substrate for human hepatic CYP3A4, was a comparatively poor substrate for human intestinal microsomes and inhibited the oxidative metabolism of saquinavir to all metabolites with a Ki of 0.2 μM. In addition, saquinavir inhibited the human, small-intestinal, microsomal CYP3A4-dependent detoxication pathway of terfenadine to its alcohol metabolite with aKi value of 0.7 μM. These data indicate that saquinavir is metabolized by human intestinal CYP3A4, that this metabolism may contribute to its poor oral bioavailability, and that combination therapy with indinavir or other protease inhibitors may attenuate its low relative bioavailability. The American Society for Pharmacology and Experimental Therapeutics