Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy

Authors

• Katherine M Robinson
• Seenae Eum
• Zeruesenay Desta
• Rachel F Tyndale
• Andrea Gaedigk
• Richard C Crist
• Cyrine E Haidar
• Alan L Myers
• Caroline F Samer
• Andrew A Somogyi
• Pablo Zubiaur
• Otito F Iwuchukwu
• Michelle Whirl-Carrillo
• Teri E Klein
• Kelly E Caudle
• Roseann S Donnelly
• Evan D Kharasch

Language

English

Publication Date

10-1-2024

Journal

Clinical Pharmacology & Therapeutics

DOI

10.1002/cpt.3338

PMID

38863207

PMCID

PMC11587193

PubMedCentral® Posted Date

6-11-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

Keywords

Humans, Analgesics, Opioid, Cytochrome P-450 CYP2B6, Genotype, Methadone, Opiate Substitution Treatment, Opioid-Related Disorders, Pharmacogenetics, Pharmacogenomic Variants

Published Open-Access

yes

Recommended Citation

Robinson, Katherine M; Eum, Seenae; Desta, Zeruesenay; et al., "Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy" (2024). Faculty, Staff and Student Publications. 196.
https://digitalcommons.library.tmc.edu/uthdb_docs/196