Role of Cytochrome P4502B6 in Methadone Metabolism and Clearance

Kharasch, Evan D.; Stubbert, Kristi

doi:10.1002/jcph.1

Cited by 66 publications

(65 citation statements)

References 39 publications

(129 reference statements)

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“…The metabolism of methadone by N-demethylation is often attributed to CYP3A4 (8,16); however, recent clinical evidence indicates that CYP2B6 may be more prominent (17). Methadone interaction studies with other HCV treatments that are potent inhibitors of CYP3A (boceprevir and telaprevir) have shown little or no effect on methadone exposure (18,19), further supporting the hypothesis that CYP3A4 is not a major CYP450 isoform involved in methadone metabolism.…”

Section: Discussionmentioning

confidence: 99%

Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy

Joseph

Schobelock

Riesenberg³

et al. 2015

Antimicrob Agents Chemother

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eThe effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC 0 -24,ss ), the steady-state maximum concentration of the drug in plasma (C max,ss ), and the steady-state concentration of the drug in plasma at 24 h (C 24,ss ) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone-and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.) I ntravenous drug abuse is currently the major source of hepatitis C virus (HCV) transmission in the United States (1, 2), with 53 to 96% of intravenous drug abusers testing positive for the anti-HCV antibody (3). In addition, approximately 67 to 96% of patients on opiate maintenance therapy, such as methadone or buprenorphine-naloxone (Suboxone), are also positive for the anti-HCV antibody (3). Faldaprevir (formerly called BI 201335) is a selective inhibitor of HCV NS3/4A protease, developed for the treatment of HCV genotype 1 infection in combination with pegylated interferon alpha 2a and ribavirin (4).Faldaprevir is metabolized primarily by cytochrome P450 3A4 (CYP3A4), and in vivo data suggest that 240 mg faldaprevir twice daily (BID) is a moderate inhibitor of CYP3A and a weak inhibitor of CYP2C9 (5). At the therapeutic dose of 120 mg once a day (QD), faldaprevir is a weak inhibitor of CYP3A and has no effect on CYP2C9 (6). Methadone hydrochloride is a synthetic opi...

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Section: Discussionmentioning

confidence: 99%

Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy

Joseph

Schobelock

Riesenberg³

et al. 2015

Antimicrob Agents Chemother

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“…Increasing the activity of CYP2B6, which metabolizes methadone stereoselectively (Gerber et al, 2004;Kharasch et al, 2004a;Totah et al, 2007Totah et al, , 2008Chang et al, 2011), increased plasma R/S methadone ratios (Kharasch et al, 2004a(Kharasch et al, , 2008a(Kharasch et al, ,c, 2012bTotah et al, 2008), whereas inhibiting CYP3A, which metabolizes methadone nonstereoselectively, did not (Kharasch et al, 2009a(Kharasch et al, ,b, 2012a. CYP2B6 inhibition by ticlopidine increased methadone enantiomers AUC and reduced methadone N-demethylation and clearance (Kharasch and Stubbert, 2013). Pharmacogenetic studies also evidence CYP2B6 involvement in methadone disposition, with CYP2B6*6/*6 homozygotes having higher dose-adjusted S-methadone plasma concentrations and/or lower dose requirements than heterozygotes or noncarriers (Crettol et al, 2006;Wang et al, 2011;Levran et al, 2013).…”

Section: Controlmentioning

confidence: 94%

“…Plasma alfentanil and fexofenadine concentrations were quantified simultaneously by solid-phase extraction and electrospray liquid chromatography-mass spectrometry as described previously (Kharasch et al, 2005). Plasma and urine methadone and EDDP enantiomer concentrations were quantified by chiral liquid chromatography-tandem electrospray mass spectrometry as described (Kharasch and Stubbert, 2013).…”

Section: Methodsmentioning

confidence: 99%

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavirlopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6-and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.

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“…Evidence derives from drug interaction and genetic studies (Greenblatt, 2014). CYP2B6 induction or inhibition correspondingly modulated methadone metabolism, clearance, and plasma concentrations (Kharasch et al, 2004(Kharasch et al, , 2008aKharasch and Stubbert, 2013b). In contrast, strong CYP3A inhibitors (Kharasch et al, 2004(Kharasch et al, , 2008a(Kharasch et al, , 2012van Heeswijk et al, 2013;Kharasch and Stubbert, 2013a) failed to diminish (and sometimes increased) methadone N-demethylation and clearance, and CYP3A induction also had no effect (Vourvahis et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Differences in Methadone Metabolism by CYP2B6 Variants

2015

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Methadone is a long-acting opioid with considerable unexplained interindividual variability in clearance. Cytochrome P450 2B6 (CYP2B6) mediates clinical methadone clearance and metabolic inactivation via N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Retrospective studies suggest that individuals with the CYP2B6*6 allelic variant have higher methadone plasma concentrations. Catalytic activities of CYP2B6 variants are highly substrate-and expression-system dependent. This investigation evaluated methadone N-demethylation by expressed human CYP2B6 allelic variants in an insect cell coexpression system containing P450 reductase. Additionally, the influence of coexpressing cytochrome b 5 , whose role in metabolism can be inhibitory or stimulatory depending on the P450 isoform and substrate, on methadone metabolism, was evaluated. EDDP formation from therapeutic (0.25-1 mM) R-and S-methadone concentrations was CYP2B6.4 ‡ CYP2B6.1 ‡ CYP2B6.5 >> CYP2B6.9 CYP2B6.6, and undetectable from CYP2B6.18. Coexpression of b 5 had small and variant-specific effects at therapeutic methadone concentrations but at higher concentrations stimulated EDDP formation by CYP2B6.1, CYP2B6.4, CYP2B6.5, and CYP2B6.9 but not CYP2B6.6. In vitro intrinsic clearances were generally CYP2B6.4 ‡ CYP2B6.1 > CYP2B6.5 > CYP2B6.9 ‡ CYP2B6.6. Stereoselective methadone metabolism (S>R) was maintained with all CYP2B6 variants. These results show that methadone N-demethylation by CYP2B6.4 is greater compared with CYP2B6.1, whereas CYP2B6.9 and CYP2B6.6 (which both contain the 516G>T, Q172H polymorphism), are catalytically deficient. The presence or absence of b 5 in expression systems may explain previously reported disparate catalytic activities of CYP2B6 variants for specific substrates. Differences in methadone metabolism by CYP2B6 allelic variants provide a mechanistic understanding of pharmacogenetic variability in clinical methadone metabolism and clearance.

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Role of Cytochrome P4502B6 in Methadone Metabolism and Clearance

Cited by 66 publications

References 39 publications

Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy

Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Differences in Methadone Metabolism by CYP2B6 Variants

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