Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Abstract

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial

“…These findings are in line with previous observations showing that pharmacokinetic factors play a marginal role for the success of methadone maintenance therapy [27, 28]. Furthermore, changes in daily methadone doses are partially associated with improved patient satisfaction in large methadone treatment facilities [29, 30].…”

OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study

“…As the responders had higher plasma levels of both S-and R-methadone concentration-to-dose ratios than the non-responders, it suggested that the cigarette smoking may be a physiological compensation for the low efficacy of methadone treatment. Similarly, Fonseca et al 50 have reported the non-responders smoked more cigarettes per day than responders in a Spanish MMT program.…”

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

“…The interactions between CYP2C19 and CYP2B6 or CYP3A4 did not show significant associations with methadone dose (data not shown), or its dose corrected plasma R-methadone or R-EDDP concentrations both in all patients and in urine opiate test negative patients (Supplementary Tables S4 and S5). As the dose of methadone may be determined by multiple genes (Fonseca et al, 2011;Hung et al, 2011), our current results indicate that the CYP2C19 GD may play a role in the N, allelic number for SNP s and subject number for gene dose; P value, permutation test p value for SNP and Kendall's coefficient of rank correlation for gene dose; (P value): p value after removing 10 subjects who had had co-medications that influence the CYP2C19 enzymatic activity (permutation test for SNP and Kendall's coefficient of rank correlation p-value for gene dose); SD, standard deviation.…”