Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT)

ABSTRACT

Background: Methadone is a substrate of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Large interindividual variability in serum methadone levels for therapeutic response has been reported. Genetic variations in ABCB1 gene may be responsible for the variability in observed methadone concentrations. Objective: This study investigated the associations of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval in opioid-dependent patients on methadone maintenance therapy (MMT). Methods: One hundred and forty-eight male opioid-dependent patients receiving MMT were recruited. Genomic deoxyribonucleic acid (DNA) was extracted from whole blood and genotyped for ABCB1 polymorphisms [i.e. 1236C>T (dbSNP rs1128503), 2677G>T/A (dbSNP rs2032582), and 3435C>T (dbSNP rs1045642)] using the allelic discrimination real-time polymerase chain reaction (PCR). Blood samples were collected at 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the dose. Serum methadone concentrations were measured using the Methadone ELISA Kit. Results: Our results revealed an association of CGC/TTT diplotype (1236C>T, 2677G>T/A, and 3435C>T) with dose-adjusted serum methadone concentration over the 24-hour dosing interval. Patients with CGC/TTT diplotype had 32.9% higher dose-adjusted serum methadone concentration over the 24-hour dosing interval when compared with those without the diplotype [mean (SD) = 8.12 (0.84) and 6.11 (0.41) ng ml⁻¹ mg⁻¹, respectively; p = 0.033]. Conclusion: There was an association between the CGC/TTT diplotype of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval among patients on MMT. Genotyping of ABCB1 among opioid-dependent patients on MMT may help individualize and optimize methadone substitution treatment.

KEYWORDS:

• ABCB1
• MDR1
• P-glycoprotein (P-gp)
• opioid dependence
• methadone maintenance therapy (MMT)
• serum methadone concentration

Acknowledgments

We thank Prof. Howard McNulty of the Institute of Pharmacy and Bio-medical Sciences University of Strathclyde, Glasgow, Scotland, for English language editing and proofreading of this article. We are grateful to Nur Amalina Che Rahim and Wan Izzati Mariah Binti Wan Hassan from Department of Pharmacy, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; Hazwan Bin Mat Din and Wan Nor Arifin Wan Harun, Biostatistics & Research Methodology Unit, School of Medical Sciences, Universiti Sains Malaysia; and all the members of Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), for their support and valuable suggestions during the study.

Funding

The study was supported by the Universiti Sains Malaysia (USM) grant under the ‘Research University Cluster (RUC)’ Grant No.1001.PSK.8620014, under the project; Application of Personalised Methadone Therapy Methadone Maintenance Therapy (PMT for MMT).

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. The authors report no relevant financial conflicts.

Additional information

Funding

The study was supported by the Universiti Sains Malaysia (USM) grant under the ‘Research University Cluster (RUC)’ Grant No.1001.PSK.8620014, under the project; Application of Personalised Methadone Therapy Methadone Maintenance Therapy (PMT for MMT).