Shibata N, Matsumura Y, Okamoto H, Kawaguchi Y, Ohtani A, Yoshikawa Y, Takada K
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
J Pharm Pharmacol. 2000 Oct;52(10):1239-46. doi: 10.1211/0022357001777379.
The drug interactions between four human immune deficiency virus (HIV-1) protease inhibitors have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration. In this study, a new HPLC analytical method developed by us was used for the simultaneous determination of saquinavir and nelfinavir in rat plasma and microsomes. The metabolic clearance rates (Vmax/Km) of saquinavir, nelfinavir, and indinavir were 170.9 +/- 10.9, 126.1 +/- 4-4, and 73.0 +/- 2.0 microL min(-1) (mg protein)(-1), respectively. Ritonavir was the strongest inhibitor with inhibition constants (Ki) of 1.64 microM for saquinavir, 0.95 microM for indinavir, and 1.01 microM for nelfinavir. Nelfinavir was the second strongest inhibitor with Ki's of 2.35 microM for saquinavir and 2.14 microM for indinavir. Indinavir was the third strongest inhibitor with Ki's of 2.76 microM for nelfinavir and 3.55 microM for saquinavir. Saquinavir was the weakest inhibitor for the other three HIV- 1 protease inhibitors. After oral co-administration in combination with another HIV-1 protease inhibitor, the AUCs of saquinavir, indinavir, and nelfinavir were significantly increased compared with mono-treatment. The AUCs of saquinavir were increased about 10.1-, 3.1- and 45.9-fold in the presence of indinavir, nelfinavir and ritonavir, respectively. The AUCs of indinavir were increased about 6.8-, 5.9- and 9.4-fold in the presence of nelfinavir, saquinavir and ritonavir, respectively. The AUCs of nelfinavir were increased about 2.2-, 6.6- and 8.5-fold in the presence of indinavir, saquinavir and ritonavir, respectively. The in-vivo effects observed after co-administration of two kinds of HIV-1 protease inhibitor were not always expected from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. These results provide useful information for the treatment of AIDS patients receiving combination therapy with two HIV-1 protease inhibitors.
四种人类免疫缺陷病毒（HIV-1）蛋白酶抑制剂之间的药物相互作用已通过使用大鼠肝微粒体组分的体外代谢研究和体内口服给药进行了表征。在本研究中，我们开发的一种新的高效液相色谱分析方法用于同时测定大鼠血浆和微粒体中的沙奎那韦和奈非那韦。沙奎那韦、奈非那韦和茚地那韦的代谢清除率（Vmax/Km）分别为170.9±10.9、126.1±4.4和73.0±2.0微升·分钟⁻¹·（毫克蛋白）⁻¹。利托那韦是最强的抑制剂，对沙奎那韦的抑制常数（Ki）为1.64微摩尔，对茚地那韦为0.95微摩尔，对奈非那韦为1.01微摩尔。奈非那韦是第二强的抑制剂，对沙奎那韦的Ki为2.35微摩尔，对茚地那韦为2.14微摩尔。茚地那韦是第三强的抑制剂，对奈非那韦的Ki为2.76微摩尔，对沙奎那韦为3.55微摩尔。沙奎那韦对其他三种HIV-1蛋白酶抑制剂的抑制作用最弱。与另一种HIV-1蛋白酶抑制剂联合口服给药后，沙奎那韦、茚地那韦和奈非那韦的AUC与单药治疗相比显著增加。在茚地那韦、奈非那韦和利托那韦存在的情况下，沙奎那韦的AUC分别增加了约10.1倍、3.1倍和45.9倍。在奈非那韦、沙奎那韦和利托那韦存在的情况下，茚地那韦的AUC分别增加了约6.8倍、5.9倍和9.4倍。在茚地那韦、沙奎那韦和利托那韦存在的情况下，奈非那韦的AUC分别增加了约2.2倍、6.6倍和8.5倍。两种HIV-1蛋白酶抑制剂联合给药后观察到的体内效应并不总是能从体外数据中预测到，这表明除了肝脏中的代谢作用外，还存在其他相互作用过程。这些结果为接受两种HIV-1蛋白酶抑制剂联合治疗的艾滋病患者的治疗提供了有用信息。
