title: ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence.
abstract: Methadone is a mu-opioid receptor agonist used for treating opiate dependence. The range of effective methadone doses is broad. Part of the large inter-individual variability in efficacy may be accounted for by genetic factors. Methadone is a substrate of the transporter P-glycoprotein (P-gp) 170 that is encoded by the ABCB1 (MDR1) gene. Thus, P-gp variants may play a role in methadone absorption and distribution. We assessed the association between ABCB1 polymorphisms and methadone dose requirements in 98 methadone-maintained patients. The stabilizing methadone doses were normally distributed with a mean and median dose of 160 mg/day (range 30-280 mg/day). Statistical analysis showed significant difference in genotype frequencies between the 'higher' (>150 mg/day) and 'lower' (< or =150 mg/day) methadone dose groups for single nucleotide polymorphism (SNP) 1236C>T (rs1128503) (experiment-wise P = 0.0325). Furthermore, individuals bearing the 3-locus genotype pattern TT-TT-TT (rs1045642, rs2032582 and rs1128503) have an approximately 5-fold chance of requiring the 'higher' methadone dose, while individuals heterozygous for these three SNPs have an approximately 3-fold chance of stabilizing at the 'lower' methadone dose (point-wise P-value = 0.026). These data suggest that specific ABCB1 variants may have clinical relevance by influencing the methadone dose required to prevent withdrawal symptoms and relapse in this population.
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA. levrano@rockefeller.edu
authors.forename: Orna
authors.initials: O
authors.lastname: Levran
authors.forename: Kimberly
authors.initials: K
authors.lastname: O'Hara
authors.forename: Einat
authors.initials: E
authors.lastname: Peles
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.forename: Sandra
authors.initials: S
authors.lastname: Barral
authors.forename: Brenda
authors.initials: B
authors.lastname: Ray
authors.forename: Lisa
authors.initials: L
authors.lastname: Borg
authors.forename: Jurg
authors.initials: J
authors.lastname: Ott
authors.forename: Miriam
authors.initials: M
authors.lastname: Adelson
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D006556:Heroin Dependence / Q000188:drug therapy*; D006801:Humans; D007557:Israel / Q000208:ethnology; D007585:Jews / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008691:Methadone / Q000008:administration & dosage* / Q000627:therapeutic use; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008691:Methadone