ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals.
OBJECTIVE
The most common treatment for opioid dependence is substitution therapy with another opioid such as methadone. The methadone dosage is individualized but highly variable, and program retention rates are low due in part to nonoptimal dosing resulting in withdrawal symptoms and further heroin craving and use. Methadone is a substrate for the P-glycoprotein transporter, encoded by the ABCB1 gene, which regulates central nervous system exposure. This retrospective study aimed to investigate the influence of ABCB1 genetic variability on methadone dose requirements.


METHODS
Genomic deoxyribonucleic acid was isolated from opioid-dependent subjects (n = 60) and non-opioid-dependent control subjects (n = 60), and polymerase chain reaction-restriction fragment length polymorphism and allele-specific polymerase chain reaction were used to determine the presence of single nucleotide polymorphisms at positions 61, 1199, 1236, 2677, and 3435. ABCB1 haplotypes were inferred with PHASE software (version 2.1).


RESULTS
There were no significant differences in the allele or genotype frequencies of the individual single nucleotide polymorphisms or haplotypes between the 2 populations. ABCB1 genetic variability influenced daily methadone dose requirements, such that subjects carrying 2 copies of the wild-type haplotype required higher doses compared with those with 1 copy and those with no copies (98.3 +/- 10.4, 58.6 +/- 20.9, and 55.4 +/- 26.1 mg/d, respectively; P = .029). In addition, carriers of the AGCTT haplotype required significantly lower doses than noncarriers (38.0 +/- 16.8 and 61.3 +/- 24.6 mg/d, respectively; P = .04).


CONCLUSIONS
Although ABCB1 genetic variability is not related to the development of opioid dependence, identification of variant haplotypes may, after larger prospective studies have been performed, provide clinicians with a tool for methadone dosage individualization.
Coller
Janet K
JK
Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide, and Department of Clinical Pharmacology, Royal Adelaide Hospital, SA, Australia. janet.coller@adelaide.edu.au
Barratt
Daniel T
DT
Dahlen
Karianne
K
Loennechen
Morten H
MH
Somogyi
Andrew A
AA
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000328:Adult; D004247:DNA / Q000235:genetics* / Q000302:isolation & purification; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008691:Methadone / Q000627:therapeutic use*; D008875:Middle Aged; D009293:Opioid-Related Disorders / Q000534:rehabilitation*; D027361:Organic Anion Transporters / Q000235:genetics*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D004247:DNA; D008691:Methadone