Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment.
OBJECTIVE
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.
Shiran
Mohammad-Reza
MR
Academic Unit of Clinical Pharmacology, University of Sheffield and Sheffield Care Trust, Substance Misuse Services, Sheffield, UK.
Lennard
Martin S
MS
Iqbal
Mohammad-Zafar
MZ
Lagundoye
Oldwale
O
Seivewright
Nicholas
N
Tucker
Geoffrey T
GT
Rostami-Hodjegan
Amin
A
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers / Q000097:blood; D002110:Caffeine / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003915:Dextromethorphan / Q000097:blood; D003917:Dextrorphan / Q000097:blood; D005260:Female; D006801:Humans; D007536:Isomerism; D008297:Male; D008691:Methadone / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D009294:Narcotics / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009293:Opioid-Related Disorders / Q000378:metabolism / Q000534:rehabilitation*; D012463:Saliva / Q000737:chemistry; D055815:Young Adult
D015415:Biomarkers; D009294:Narcotics; D003917:Dextrorphan; D002110:Caffeine; D003915:Dextromethorphan; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D008691:Methadone