von Moltke L L, Greenblatt D J, Grassi J M, Granda B W, Duan S X, Fogelman S M, Daily J P, Harmatz J S, Shader R I
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
J Clin Pharmacol. 1998 Feb;38(2):106-11. doi: 10.1002/j.1552-4604.1998.tb04398.x.
Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450-3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450-2C9 (tolbutamide hydroxylation), -2C19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O-demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450-1A2 (phenacetin O-deethylation) or -2E1 (chlorzoxazone hydroxylation). Thus, among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.
使用基于人肝微粒体的体外模型，对四种蛋白酶抑制剂抗病毒药物（利托那韦、茚地那韦、奈非那韦、沙奎那韦）作为六种人细胞色素活性的体外抑制剂进行了评估。利托那韦是P450 - 3A活性（三唑仑羟基化）的高效抑制剂，其抑制效力略低于酮康唑。茚地那韦也是一种强效的3A抑制剂，而奈非那韦和沙奎那韦的效力较低。利托那韦对细胞色素P450 - 2C9（甲苯磺丁脲羟基化）、- 2C19（S - 美芬妥因羟基化）和 - 2D6（右美沙芬O - 去甲基化和地昔帕明羟基化）具有高抑制效力，而其他蛋白酶抑制剂对这些反应的抑制活性低一个或多个数量级。这些蛋白酶抑制剂均对P450 - 1A2（非那西丁O - 脱乙基化）或 - 2E1（氯唑沙宗羟基化）没有重要的抑制效力。因此，在现有的蛋白酶抑制剂中，利托那韦因抑制细胞色素P450活性而导致药物相互作用的风险最高。
