Human Molecular Genetics Advance Access published online on April 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn122
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ABCB1 (MDR1) Genetic Variants are Associated with Methadone Doses Required for Effective Treatment of Heroin Dependence
1 Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA 2 Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse, Treatment and Research, Tel Aviv Elias Sourasky Medical Center, Tel Aviv 64924, Israel 3 Laboratory of Statistical Genetics, The Rockefeller University, New York, NY 10065, USA 4 Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
* To whom correspondence should be addressed at: The Rockefeller University, Laboratory of the Biology of Addictive Diseases, Box 171, New York, NY 10065, USA. Tel: (212) 327-8282; fax (212) 327-7023; Email: levrano{at}rockefeller.edu
Received October 1, 2007; Revised February 29, 2008; Accepted April 11, 2008
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 170 (P-gp) 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 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.