Iribarne C, Berthou F, Carlhant D, Dreano Y, Picart D, Lohezic F, Riche C
Laboratoires de Biochimie-Nutrition EA948, Faculte de Medecine, Brest, France.
Drug Metab Dispos. 1998 Mar;26(3):257-60.
Ritonavir, indinavir, and saquinavir, all human immunodeficiency virus-1 protease inhibitors with a potent antiviral effect during triple therapy, are extensively metabolized by liver cytochrome P450 3A4. As this P450 isoform is involved in the metabolism of about 50% of drugs, coadministration of protease inhibitors with other drugs may lead to serious effects due to enzyme inhibition. Among these drugs, methadone and buprenorphine, both metabolized by P450 3A4, are potential candidates to drug interactions. In this study, metabolic interactions between these protease inhibitors and methadone or buprenorphine were studied in vitro in a panel of 13 human liver microsomes. Ritonavir was the most potent competitive inhibitor with Ki about 50 and 20 nM for methadone and buprenorphine metabolisms, respectively. Indinavir and saquinavir also inhibited methadone N-demethylation (Ki about 3 and 15 microM, respectively) and buprenorphine N-dealkylation (Ki about 0.8 and 7 microM, respectively). The rank order of inhibition potency against metabolism of methadone and buprenorphine was ritonavir > indinavir > saquinavir. There is obvious potential for clinically significant drug interactions, particularly with ritonavir. In brief, caution should be advised if human immunodeficiency virus-1 protease inhibitors are coadministered with methadone and buprenorphine.
利托那韦、茚地那韦和沙奎那韦均为人类免疫缺陷病毒1型蛋白酶抑制剂，在三联疗法中具有强效抗病毒作用，它们主要通过肝脏细胞色素P450 3A4进行广泛代谢。由于这种P450同工酶参与了约50%药物的代谢，蛋白酶抑制剂与其他药物合用可能因酶抑制作用而导致严重后果。在这些药物中，美沙酮和丁丙诺啡均通过P450 3A4代谢，是药物相互作用的潜在候选药物。在本研究中，在一组13个人类肝微粒体中对这些蛋白酶抑制剂与美沙酮或丁丙诺啡之间的代谢相互作用进行了体外研究。利托那韦是最有效的竞争性抑制剂，对美沙酮和丁丙诺啡代谢的抑制常数（Ki）分别约为50 nM和20 nM。茚地那韦和沙奎那韦也抑制美沙酮的N-去甲基化（Ki分别约为3 μM和15 μM）和丁丙诺啡的N-脱烷基化（Ki分别约为0.8 μM和7 μM）。对美沙酮和丁丙诺啡代谢抑制效力的排序为利托那韦>茚地那韦>沙奎那韦。临床上存在明显的药物相互作用可能性，尤其是与利托那韦。简而言之，如果人类免疫缺陷病毒1型蛋白酶抑制剂与美沙酮和丁丙诺啡合用，应谨慎使用。
