Fitzsimmons M E, Collins J M
Laboratory of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD 20850, USA.
Drug Metab Dispos. 1997 Feb;25(2):256-66.
Saquinavir is a HIV 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 K(M) values of 0.3-0.5 microM. 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 6beta-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 microM. In addition, saquinavir inhibited the human, small-intestinal, microsomal CYP3A4-dependent detoxication pathway of terfenadine to its alcohol metabolite with a Ki value of 0.7 microM. 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.
沙奎那韦是一种用于治疗获得性免疫缺陷综合征患者的HIV蛋白酶抑制剂，但其应用受到口服生物利用度低的限制。在17种不同的人小肠微粒体制剂中评估了人肠组织代谢沙奎那韦的潜力。沙奎那韦被人小肠微粒体代谢为多种单羟基化和二羟基化产物，其米氏常数（K(M)）值为0.3 - 0.5微摩尔。主要代谢产物M - 2和M - 7分别是八氢 - 2 - (1H) - 异喹啉基和(1,1 - 二甲基乙基)氨基上的单羟基化产物。酮康唑和三乙酰竹桃霉素，细胞色素P4503A4（CYP3A4）的选择性抑制剂，是沙奎那韦所有氧化代谢产物的强效抑制剂。细胞色素P450选择性抑制剂呋拉茶碱、氟伏沙明、磺胺苯吡唑、美芬妥英、奎尼丁和氯唑沙宗的抑制作用很小。所有沙奎那韦代谢产物与睾酮6β - 羟基化高度相关且相互之间高度相关。人肝微粒体和重组CYP3A4将沙奎那韦氧化为与人小肠微粒体观察到的相同代谢谱。茚地那韦是一种强效HIV蛋白酶抑制剂且是人肝CYP3A4的底物，是人肠微粒体相对较差的底物，并且以0.2微摩尔的抑制常数（Ki）抑制沙奎那韦向所有代谢产物的氧化代谢。此外，沙奎那韦以0.7微摩尔的Ki值抑制人小肠微粒体中特非那定依赖CYP3A4的解毒途径生成其醇代谢产物。这些数据表明沙奎那韦被人肠CYP3A4代谢，这种代谢可能导致其口服生物利用度差，并且与茚地那韦或其他蛋白酶抑制剂的联合治疗可能减轻其低相对生物利用度。
