| Title | The effect of rifampin and nelfinavir on the metabolism of methadone and buprenorphine in primary cultures of human hepatocytes. | | Author(s) | Moody DE, Fang WB, Lin SN, Weyant DM, Strom SC, Omiecinski CJ | | Institution | 1 University of Utah; | | Source | Drug Metab Dispos 2009 Sep 22. | | Abstract | We tested the hypothesis that primary cultures of human hepatocytes could predict potential drug interactions with methadone and buprenorphine. Hepatocytes (5 donors) were preincubated with DMSO (vehicle), rifampin or nelfinavir prior to incubation with methadone or buprenorphine. Culture media (0-60 minute) was analyzed by liquid chromatography-tandem mass spectrometry for R- and S-methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-dipehylpyrrolidine (EDDP) or for buprenorphine, norbuprenorphine, and their glucuronides (B-3-G and N-3-G). R- and S-EDDP were detected in 3/5, 4/5 and 5/5 media from cells pretreated with DMSO, nelfinavir and rifampin. R-EDDP increased 3.1- and 26.5-fold, and S-EDDP 2.5- and 21.3-fold after nelfinavir and rifampin. The rifampin effect was significant. B-3-G production was detected in media of all cells incubated with buprenorphine, and accounted for most buprenorphine loss from culture media; it was not significantly affected by either pretreatment. Norbuprenorphine and N-3-G together were detected in 3/5, 4/5 and 5/5 donors pretreated with DMSO, nelfinavir and rifampin; norbuprenorphine in 1/5, 1/5 and 2/5. While there was a trend for norbuprenorphine (2.8-, 4.9-fold) and N-3-G (1.7-, 1.9-fold) to increase after nelfinavir and rifampin, none of the changes were significant. To investigate low norbuprenorphine production, buprenorphine was incubated with human liver and small intestine microsomes fortified to support both N-dealkylation and glucurondation; N-dealkylation predominated in small intestine, glucuronidation in liver microsomes. These studies support the hypothesis that methadone metabolism and its potential for drug interactions can be predicted with cultured human hepatocytes, but for buprenorphine, combined effects of hepatic and small intestinal metabolism are likely involved. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19773542 |
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