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ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence

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 th...

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Bibliographic Details
Published in:Human molecular genetics 2008-07, Vol.17 (14), p.2219-2227
Main Authors: Levran, Orna, O'Hara, Kimberly, Peles, Einat, Li, Dawei, Barral, Sandra, Ray, Brenda, Borg, Lisa, Ott, Jurg, Adelson, Miriam, Kreek, Mary Jeanne
Format: Article
Language:English
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Summary: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’ (≤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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddn122