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

Orna Levran*, Kimberly O'Hara, Einat Peles, Dawei Li, Sandra Barral, Brenda Ray, Lisa Borg, Jurg Ott, Miriam Adelson, Mary Jeanne Kreek

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

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' (≤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.

Original languageEnglish
Pages (from-to)2219-2227
Number of pages9
JournalHuman Molecular Genetics
Volume17
Issue number14
DOIs
StatePublished - Jul 2008
Externally publishedYes

Funding

FundersFunder number
Chinese Government
NCRR-CTSAUL1-RR024143
National Institutes of HealthMH-R01-44292, DA-K05 -00049, DA-P60-05130
National Center for Research ResourcesUL1RR024143
Rockefeller University
National Natural Science Foundation of China30730057

    Fingerprint

    Dive into the research topics of 'ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence'. Together they form a unique fingerprint.

    Cite this