Effect of Rifampin and Nelfinavir on the Metabolism of Methadone and Buprenorphine in Primary Cultures of Human Hepatocytes

Abstract

ABSTRACT:We tested the hypothesis that primary cultures of human hepatocytes could predict potential drug interactions with methadone and buprenorphine. Hepatocytes (five donors) were preincubated with dimethyl sulfoxide (DMSO) (vehicle), rifampin, or nelfinavir before incubation with methadone or buprenorphine. Culture media (0-60 min) was analyzed by liquid chromatography-tandem mass spectrometry for R-and S-methadone and R-and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) or for buprenorphine, norbuprenorphine, and their glucuronides [buprenorphine-3-glucuronide (B-3-G) and norbuprenorphine-3-glucuronide (N-3-G)]. R-and S-EDDP were detected in three of five, four of five, and five of five media from cells pretreated with DMSO, nelfinavir, and rifampin. R-EDDP increased 3.1-and 26.5-fold, and S-EDDP increased 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 of the buprenorphine loss from culture media; it was not significantly affected by either pretreatment. Norbuprenorphine and N-3-G together were detected in three of five, four of five, and five of five donors pretreated with DMSO, nelfinavir and rifampin, and norbuprenorphine in one of five, one of five, and two of five donors. Although there was a trend for norbuprenorphine (2.8-and 4.9-fold) and N-3-G (1.7-and 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 glucuronidation; N-dealkylation predominated in small intestine and 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 the combined effects of hepatic and small intestinal metabolism are probably involved.

Gender differences in pharmacokinetics of maintenance dosed buprenorphine

“…As total blood flow to the liver is higher in males (Williams and Leggett, 1989), this may contribute to the gender difference. The fact that a corresponding increase in norbuprenorphine was not seen with the decreased buprenorphine in males, may be related to our proposal that buprenorphine N-dealkylation occurs primarily in the small intestine (Moody et al, 2009b). …”

Treating Chronic Pain: An Overview of Clinical Studies Centered on the Buprenorphine Option

“…Ketoconazole, a strong inhibitor of CYP3A4, does not influence buprenorphine plasma clearance, as measured by the area under the curve of timed plasma levels [76, 101, 102]. Drugs such as atazanavir, which block both CYP3A4 and UGT1A1, increase buprenorphine levels [76], while drugs that induce CYP3A4, such as the classical antiseizure medications carbamazepine and rifampin, increase clearance and can lead to poor pain control [103, 104].…”

Survey of methadone-drug interactions among patients of methadone maintenance treatment program in Taiwan

“…The most dangerous side effect of methadone is torsade de pointes (TdP) [ 18 - 22 ], which may threaten a patient's life. MDIs can either increase [ 23 ] or decrease [ 24 ] serum methadone levels, leading to treatment failure or even death [ 19 , 25 ]. Therefore, proper methadone dose adjustment and therapeutic drug monitoring should be handled with caution when MMTP patients also have received other medicines that could yield TdP or interfere with the activities of cytochrome P 450 (CYP450) enzymes, such as 3A4 [ 26 ], 2B6 [ 26 , 27 ], 2C19 [ 27 ] or 2D6 [ 28 ].…”

“…However, most patients participated in these studies were from Western societies and, therefore, are limited to Caucasian or African origins [ 32 - 35 ]. In addition, many, if not most, studies focused on the interactions of anti-retroviral agents and methadone among HIV patients in MMTP [ 24 , 29 - 31 , 34 - 36 ]. Furthermore, these studies were mostly based on reviews of medical or pharmacy records, and therefore may be limited by incomplete information and recall bias.…”