Methadone used for opioid use disorder has a highly variable half-life (8–59 hours) between patients. A significant pharmacogenomic contributor to this variability is polymorphism in which enzyme, and what clinical risk results from slow metabolizers receiving standard doses?
- A CYP2D6 polymorphism; slow metabolizers have poor analgesic response
- B CYP2B6 polymorphism (especially CYP2B6*6 allele); slow metabolizers accumulate methadone causing QT prolongation and torsades de pointes ✓
- C CYP3A4 polymorphism; slow metabolizers develop respiratory depression within 30 minutes
- D UGT2B7 polymorphism; slow metabolizers have elevated glucuronide metabolites causing myoclonus
Explanation
Methadone is metabolized primarily by CYP2B6, with secondary contributions from CYP3A4 and CYP2D6. The CYP2B6*6 variant allele (c.516G>T/c.785A>G) is the most important pharmacogenomic determinant of methadone plasma levels; individuals homozygous for *6 are poor metabolizers with significantly elevated methadone concentrations. Because methadone also blocks hERG (IKr) channels, elevated concentrations directly prolong the QTc interval, with risk of torsades de pointes — a potentially fatal arrhythmia. This QT risk is most pronounced in CYP2B6 slow metabolizers and explains why patients require individualized dosing and ECG monitoring during methadone initiation.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.