title: Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels:  a CYP2B6 gene resequencing study.
abstract: BACKGROUND
  (S)-Methadone, metabolized mainly by CYP2B6, shows a wide interindividual variability in its pharmacokinetics and pharmacodynamics.
  
  
  METHODS
  Resequencing of the CYP2B6 gene was performed in 12 and 35 selected individuals with high (S)-methadone plasma exposure and low (S)-methadone plasma exposure, respectively, from a previously described cohort of 276 patients undergoing methadone maintenance treatment. Selected genetic polymorphisms were then analyzed in the complete cohort.
  
  
  RESULTS
  The rs35303484 (*11; c136A>G; M46V) polymorphism was overrepresented in the high (S)-methadone level group, whereas the rs3745274 (*9; c516G>T; Q172H), rs2279344 (c822+183G>A), and rs8192719 (c1294+53C>T) polymorphisms were underrepresented in the low (S)-methadone level group, suggesting an association with decreased CYP2B6 activity. Conversely, the rs3211371 (*5; c1459C>T; R487C) polymorphism was overrepresented in the low-level group, indicating an increased CYP2B6 activity. A higher allele frequency was found in the high-level group compared with the low-level group for rs3745274 (*9; c516G>T; Q172H), rs2279343 (*4; c785A>G; K262R) (together representing CYP2B6*6), rs8192719 (c1294+53C>T), and rs2279344 (c822+183G>A), suggesting their involvement in decreased CYP2B6 activity. These results should be replicated in larger independent cohorts.
  
  
  CONCLUSIONS
  Known genetic polymorphisms in CYP2B6 contribute toward explaining extreme (S)-methadone plasma levels observed in a cohort of patients following methadone maintenance treatment.
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Centre for Psychiatric Neurosciences,University Hospital Center, University of Lausanne, Lausanne.
authors.forename: Maria
authors.initials: M
authors.lastname: Dobrinas
authors.forename: Séverine
authors.initials: S
authors.lastname: Crettol
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oneda
authors.forename: Rachel
authors.initials: R
authors.lastname: Lahyani
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.forename: Eva
authors.initials: E
authors.lastname: Choong
authors.forename: Rubin
authors.initials: R
authors.lastname: Lubomirov
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D000483:Alleles; D000701:Analgesics, Opioid / Q000097:blood* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002853:Chromatography, Liquid; D015331:Cohort Studies; D065702:Cytochrome P-450 CYP2B6; D005838:Genotype; D006801:Humans; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D008691:Methadone / Q000097:blood* / Q000493:pharmacokinetics; D009293:Opioid-Related Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014018:Tissue Distribution
chemical_list: D000701:Analgesics, Opioid; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D008691:Methadone