ArticleDrug metabolism and disposition: the biological fate of chemicals2013
Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Pooled it
- Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition.Clinical pharmacology and therapeutics · 2019Trial
- Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism.Anesthesiology · 2015Trial
- Fetal and Infant Effects of Maternal Opioid Use during Pregnancy: A Literature Review including Clinical, Toxicological, Pharmacogenomic, and Epigenetic Aspects for Forensic Evaluation.Children (Basel, Switzerland) · 2024Review
- Influence ofLife (Basel, Switzerland) · 2023Article
- Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone.Drug metabolism and pharmacokinetics · 2022Article
- Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition.British journal of clinical pharmacology · 2022Article
- Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans.Journal of personalized medicine · 2021Article
- Article
- Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry.Drug metabolism and disposition: the biological fate of chemicals · 2019Review
- Methadone Disposition: Implementing Lessons Learned.Journal of clinical pharmacology · 2019Article
- Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes.Pharmacology research & perspectives · 2019Article
- Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics.Biochemical pharmacology · 2018Review
- Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction.Journal of cellular and molecular medicine · 2017Article
- Current Concepts in Methadone Metabolism and Transport.Clinical pharmacology in drug development · 2017Article
- Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays.BioMed research international · 2017Review
- Genetic determinants of fetal opiate exposure and risk of neonatal abstinence syndrome: Knowledge deficits and prospects for future research.Clinical pharmacology and therapeutics · 2015Review
- Differences in Methadone Metabolism by CYP2B6 Variants.Drug metabolism and disposition: the biological fate of chemicals · 2015Article
- In silico ordinary differential equation/partial differential equation hemodialysis model estimates methadone removal during dialysis.Journal of pain research · 2015Article
- Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics.Anesthesiology · 2014Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The long-acting opioid methadone displays considerable unexplained interindividual pharmacokinetic variability. Methadone metabolism clinically occurs primarily by N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), catalyzed predominantly by CYP2B6. Retrospective studies suggest that the common allele variant CYP2B6*6 may influence methadone plasma concentrations. The catalytic activity of CYP2B6.6, encoded by CYP2B6*6, is highly substrate-dependent. This investigation compared methadone N-demethylation by CYP2B6.6 with that by wild-type CYP2B6.1. Methadone enantiomer and racemate N-demethylation by recombinant-expressed CYP2B6.6 and CYP2B6.1 was determined. At substrate concentrations (0.25-2 µM) approximating plasma concentrations occurring clinically, rates of methadone enantiomer N-demethylation by CYP2B6.6, incubated individually or as the racemate, were one-third to one-fourth those by CYP2B6.1. For methadone individual enantiomers and metabolism by CYP2B6.6 compared with CYP2B6.1, Vmax was diminished, Ks was greater and the in vitro intrinsic clearance was diminished 5- to 6-fold. The intrinsic clearance for R- and S-EDDP formation from racemic methadone was diminished approximately 6-fold and 3-fold for R- and S-methadone, respectively. Both CYP2B6.6 and CYP2B6.1 showed similar stereoselectivity (S>R-methadone). Human liver microsomes with diminished CYP2B6 content due to a CYP2B6*6 allele had lower rates of methadone N-demethylation. Results show that methadone N-demethylation catalyzed by CYP2B6.6, the CYP2B6 variant encoded by the CYP2B6*6 polymorphism, is catalytically deficient compared with wild-type CYP2B6.1. Diminished methadone N-demethylation by CYP2B6.6 may provide a mechanistic explanation for clinical observations of altered methadone disposition in individuals carrying the CYP2B6*6 polymorphism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.