INHIBITION OF METHADONE AND BUPRENORPHINE N-DEALKYLATIONS BY 3 HIV-1 PROTEASE INHIBITORS

Ritonavir, indinavir, and saquinavir, all human immunodeficiency virus -1 protease inhibitors with a potent antiviral effect during triple th erapy, are extensively metabolized by liver cytochrome P450 3A4. As th is P450 isoform is involved in the metabolism of about 50% of drugs, c oadministration of protease inhibitors with other drugs may lead to se rious effects due to enzyme inhibition. Among these drugs, methadone a nd buprenorphine, both metabolized by P450 3A4, are potential candidat es 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 m ost potent competitive inhibitor with K-i about 50 and 20 nM for metha done and buprenorphine metabolisms, respectively. Indinavir and saquin avir also inhibited methadone N-demethylation (K-i about 3 and 15 mu M , respectively) and buprenorphine N-dealkylation (K-i about 0.8 and 7 mu M, respectively), The rank order of inhibition potency against meta bolism of methadone and buprenorphine was ritonavir > indinavir > saqu inavir. There is obvious potential for clinically significant drug int eractions, particularly with ritonavir. In brief, caution should be ad vised if human immunodeficiency virus-1 protease inhibitors are coadmi nistered with methadone and buprenorphine.