title: Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment.
abstract: 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.
authors.affiliation: Academic Unit of Clinical Pharmacology, University of Sheffield and Sheffield Care Trust, Substance Misuse Services, Sheffield, UK.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Shiran
authors.forename: Martin S
authors.initials: MS
authors.lastname: Lennard
authors.forename: Mohammad-Zafar
authors.initials: MZ
authors.lastname: Iqbal
authors.forename: Oldwale
authors.initials: O
authors.lastname: Lagundoye
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seivewright
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Tucker
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: 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
chemical_list: 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