C. Iribarne et al., INHIBITION OF METHADONE AND BUPRENORPHINE N-DEALKYLATIONS BY 3 HIV-1 PROTEASE INHIBITORS, Drug metabolism and disposition, 26(3), 1998, pp. 257-260
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.