TY - JOUR T1 - Inhibition of Methadone and Buprenorphine<em>N</em>-Dealkylations by Three HIV-1 Protease Inhibitors JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 257 LP - 260 VL - 26 IS - 3 AU - Christelle Iribarne AU - François Berthou AU - Dominique Carlhant AU - Yvonne Dreano AU - Daniel Picart AU - Françoise Lohezic AU - Christian Riche Y1 - 1998/03/01 UR - http://dmd.aspetjournals.org/content/26/3/257.abstract N2 - 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 μM, respectively) and buprenorphine N-dealkylation (Ki about 0.8 and 7 μM, respectively). The rank order of inhibition potency against metabolism of methadone and buprenorphine was ritonavir &gt; indinavir &gt; 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. The American Society for Pharmacology and Experimental Therapeutics ER -