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Human Molecular Genetics Advance Access originally published online on April 17, 2008
Human Molecular Genetics 2008 17(14):2219-2227; doi:10.1093/hmg/ddn122
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Orna Levran1,*, Kimberly O'Hara1, Einat Peles3, Dawei Li2, Sandra Barral2, Brenda Ray1, Lisa Borg1, Jurg Ott2,4, Miriam Adelson1,3 and Mary Jeanne Kreek1

1 Laboratory of the Biology of Addictive Diseases 2 Laboratory of Statistical Genetics, The Rockefeller University, New York, NY 10065, USA 3 Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse, Treatment and Research, Tel Aviv Elias Sourasky Medical Center, Tel Aviv 64924, Israel 4 Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, PR China

* To whom correspondence should be addressed. Tel: +1 2123278282; Fax: +1 2123277023; 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 (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.


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