Drug interactions with methadone: Time to revise the product label

Greenblatt, David J.

doi:10.1002/cpdd.137

Cited by 17 publications

(24 citation statements)

References 27 publications

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“…21,39-43 Nonetheless, it is now established, after recognizing CYP2B6 as a major catalyst of methadone metabolism in vitro , 28,44-47 and from numerous clinical drug interaction studies, that CYP2B6, not CYP3A4, is the principle determinant of methadone elimination. 3,14-16 Specifically, neither CYP3A induction 48 nor strong inhibition 13,14,28,29,31 altered methadone N-demethylation or clearance, while CYP2B6 induction 13,28,32,46 or inhibition 15,49 did correspondingly modulate methadone elimination. CYP2B6 allelic influences on plasma R/S methadone ratios further demonstrate the role of CYP2B6.…”

Section: Discussionmentioning

confidence: 94%

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Methadone Pharmacogenetics

et al. 2015

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Background Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. Methods Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n=21), CYP2B6*1/*6 (n=20), and CYP2B6*6/*6 (n=17), and also CYP2B6*1/*4 (n=1), CYP2B6*4/*6 (n=3), CYP2B6*5/*5 (n=2) subjects received single doses of intravenous and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. Results Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1, and R-methadone apparent oral clearance was 25 and 30% lower. R- and S-methadone apparent oral clearance was 3- and 4-fold greater in CYP2B6*4 carriers. Intravenous and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with CYP2B6*1 homozygotes, and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African-Americans due to the CYP2B6*6 genetic polymorphism. Conclusions CYP2B6 polymorphisms influence methadone plasma concentrations, due to altered methadone metabolism and thus clearance. Genetic influence is greater for oral than intravenous, and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.

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Section: Discussionmentioning

confidence: 94%

“…CYP2B6 is the principle determinant of clinical methadone elimination. 3,13-16 This recent recognition has necessitated a paradigm shift in therapeutic use, and motivates renewed quests for understanding variability in methadone disposition.…”

Section: Introductionmentioning

confidence: 99%

Methadone Pharmacogenetics

et al. 2015

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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).…”

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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“…Initial in vitro studies identified CYP3A4 as metabolizing methadone, and subsequently, by extrapolation, CYP3A4 was assumed for more than a decade to be responsible for clinical methadone metabolism and clearance. However, it has now been established, subsequent to the discovery of the isoenzyme, that CYP2B6 is also a major catalyst of methadone metabolism in vitro . Numerous clinical drug interaction and pharmacogenetic studies have definitively illustrated that CYP2B6, not CYP3A4, is the principal determinant of methadone metabolism, elimination, and plasma concentrations.…”

Section: Highlights Of Individual Presentationsmentioning

confidence: 99%

Drug–Drug Interactions and Diagnostics for Drug Users With HIV and HIV/HCV Coinfections: Introduction

Khalsa

Talal

Morse

2017

Clinical Pharm in Drug Dev

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Substance use and pharmacologic treatment of co-occurring infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are associated with many adverse consequences including pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs). The National Institute on Drug Abuse sponsored a 2-day conference on DDIs at which clinicians/scientists from government, academia, and the pharmaceutical industry presented the most current research findings to formulate a comprehensive overview of DDIs. Specific topics discussed included drug metabolism; drug interactions between medications used in the treatment of HIV, HCV, and substance use disorders; intrahepatic concentrations and methods of assessment of drugs in liver disease of varying etiologies and degrees of impairment; and minimally invasive sampling techniques for the assessment of intrahepatic drug concentrations, viral replication, and changes in gene expression in response to treatment. Finally, the speakers identified research targets and priorities on DDIs. Areas of emphasis included development of diagnostic assays for drug concentration assessment in different organs, an enhanced understanding of factors responsible for alterations in drug metabolism and excretion, and establishment of clinical trials and work groups to study DDIs. Our long-term objective is to broaden investigation in the field of DDIs in substance users.

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Drug interactions with methadone: Time to revise the product label

Cited by 17 publications

References 27 publications

Methadone Pharmacogenetics

Methadone Pharmacogenetics

Differences in Methadone Metabolism by CYP2B6 Variants

Drug–Drug Interactions and Diagnostics for Drug Users With HIV and HIV/HCV Coinfections: Introduction

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