ArticleBasic & clinical pharmacology & toxicology2011
Stereo-selective metabolism of methadone by human liver microsomes and cDNA-expressed cytochrome P450s: a reconciliation.
Article in Basic & clinical pharmacology & toxicology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 96 citations in OpenAlex.
- Population Genetic-Based Pharmacokinetic Modeling of Methadone and its Relationship with the QTc Interval in Opioid-Dependent Patients.Clinical pharmacokinetics · 2016Trial
- Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism.Anesthesiology · 2015Trial
- Pharmacometric modeling of opioid disposition in pregnancy: a systematic review of PopPK and PBPK approaches, model limitations, and future directions.Frontiers in pharmacology · 2026Review
- The Relevance of Pharmacokinetic Biomarkers in Response to Methadone Treatment: A Systematic Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Natural Products Inhibition of Cytochrome P450 2B6 Activity and Methadone Metabolism.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- Identifying Clinically Relevant Drug-Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection.Clinical pharmacology and therapeutics · 2022Article
- In vitro-in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans.Archives of toxicology · 2022Article
- A genetic-based population PK/PD modeling of methadone in Chinese opiate dependence patients.European journal of clinical pharmacology · 2022Article
- The Risk of Ventricular Dysrhythmia or Sudden Death in Patients Receiving Serotonin Reuptake Inhibitors With Methadone: A Population-Based Study.Frontiers in pharmacology · 2022Article
- Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children.CPT: pharmacometrics & systems pharmacology · 2021Article
- Novel associations betweenPharmacogenomics · 2021Observational
- Add-On Selective Estrogen Receptor Modulators for Methadone Maintenance Treatment.Frontiers in endocrinology · 2021Article
- Pharmacogenomics of methadone: a narrative review of the literature.Pharmacogenomics · 2020Review
- Precision therapeutic opioid dosing implications from genetic biomarkers and craving score.Medicine · 2020Article
- Article
- Effects ofFrontiers in public health · 2019Article
- Human Enzymes for Organic Synthesis.Angewandte Chemie (International ed. in English) · 2018Review
- Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics.Biochemical pharmacology · 2018Review
- Practical Pharmacology of Methadone: A Long-acting Opioid.Indian journal of palliative care · 2018Review
- Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities.Journal of analytical toxicology · 2017Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
In vitro metabolism of methadone was investigated in cytochrome P450 (CYP) supersomes and phenotyped human liver microsomes (HLMs) to reconcile past findings on CYP involvement in stereo-selective metabolism of methadone. Racaemic methadone was used for incubations; (R)- and (S)-methadone turnover and (R)- and (S)-EDDP formation were determined using chiral liquid chromatography-tandem mass spectrometry. CYP supersome activity for methadone use and EDDP formation ranked CYP2B6 > 3A4 > 2C19 > 2D6 > 2C18, 3A7 > 2C8, 2C9, 3A5. After abundance scaling, CYP3A4, 2B6 and 2C19 accounted for 63-74, 12-32 and 1. 4-14% of respective activity. CYP2B6, 2D6 and 2C18 demonstrated a preference for (S)-EDDP formation; CYP2C19, 3A7 and 2C8 for (R)-EDDP; 3A4 none. Correlation analysis with 15 HLMs supported the involvement of CYP2B6 and 3A. The significant correlation of S/R ratio with CYP2B6 activity confirmed its stereo-selectivity. CYP2C19 and 2D6 inhibitors and monoclonal antibody (mAb) did not inhibit EDDP formation in HLM. Chemical and mAb inhibition of CYP3A in high 3A activity HLM reduced EDDP formation by 60-85%; inhibition of CYP2B6 in 2B6 high-activity HLM reduced (S)-EDDP formation by 80% and (R)-EDDP formation by 55%. Inhibition changed methadone metabolism in a stereo-selective manner. When CYP3A was inhibited, 2B6 mediated (S)-EDDP formation predominated; S/R stereo-selectivity increased. When 2B6 was inhibited (S)-EDDP formation fell and stereo-selectivity decreased. The results confirmed the primary roles of CYPs 3A4 and 2B6 in methadone metabolism; CYP2C8 and 2C9 did not appear involved; 2C19 and 2D6 have minimal roles. CYP2B6 is the primary determinant of stereo-selective metabolism; stereo-selective inhibition might play a role in varied plasma concentrations of the two enantiomers.
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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.