Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment

• Published in: British journal of clinical pharmacology 2009-01, Vol.67 (1), p.29-37
• Main Authors: Shiran, Mohammad‐Reza, Lennard, Martin S., Iqbal, Mohammad‐Zafar, Lagundoye, Oldwale, Seivewright, Nicholas, Tucker, Geoffrey T., Rostami‐Hodjegan, Amin
• Format: Article
• Language: English
• Subjects: Adult; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Biomarkers - blood; Caffeine - metabolism; CYP1A2; CYP2D6; CYP3A4; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A - metabolism; Dextromethorphan - blood; Dextrorphan - blood; Female; Humans; Isomerism; Male; Medical sciences; methadone; Methadone - blood; Methadone - pharmacokinetics; Methadone - therapeutic use; midazolam; Midazolam - metabolism; Middle Aged; Narcotics - blood; Narcotics - pharmacokinetics; Narcotics - therapeutic use; Opioid-Related Disorders - metabolism; Opioid-Related Disorders - rehabilitation; Pharmacokinetics; Pharmacology. Drug treatments; Saliva - chemistry; Young Adult
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2008.03312.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several cytochromes P450 (CYPs) have been implicated in the metabolism of methadone, but there is no consensus on their relative contributions to overall disposition and hence variability in response. WHAT THIS STUDY ADDS • Variability in CYP3A4 activity has statistically significant but nonetheless modest influence on the oral clearance of methadone and its enantiomers. • However, CYPs 1A2 and 2D6 appear to have no impact at all. AIMS To investigate the influence of different cytochrome P450 (CYP) activities and other potential covariates on the disposition of methadone in patients on methadone maintenance therapy (MMT). METHODS Eighty‐eight patients (58 male; 21–55 years; 84 White) on MMT were studied. CYP2D6 activity [3 h plasma metabolic ratio of dextromethorphan (DEX) to dextrorphan (DOR)] was determined in 44 patients (29 male; 24–55 years), CYP1A2 activity (salivary caffeine elimination half‐life) in 44 patients (21 male; 24–55 years) and CYP3A activity (oral clearance of midazolam) in 49 patients (33 male; 23–55 years). Data on all three CYPs were obtained from 32 subjects. Total plasma concentrations of (RS)‐methadone and total and unbound plasma concentrations of both enantiomers were measured by LC/MS. Population pharmacokinetics and subsequent multiple regression analysis were used to calculate methadone oral clearance and to identify its covariates. RESULTS Between 61 and 68% of the overall variation in total plasma trough concentrations of (RS)‐, (R)‐ and (S)‐methadone was explained by methadone dose, duration of addiction before starting MMT, CYP3A activity and illicit morphine use. CYP3A activity explained 22, 16, 15 and 23% of the variation in unbound (R)‐, unbound (S)‐, total (RS)‐ and total (S)‐methadone clearances, respectively. Neither CYP2D6 nor CYP1A2 activity was related to methadone disposition. CONCLUSIONS CYP3A activity has a modest influence on methadone disposition. Inhibitors and inducers of this enzyme should be monitored in patients taking methadone.