Population Differences in the Genetic Polymorphism of CYP2B6 May Impact on the Pharmacology of MMT

Nasir, Mohamad and Nurfadhlina, Musa and Sean, Tan (2015) Population Differences in the Genetic Polymorphism of CYP2B6 May Impact on the Pharmacology of MMT. PUBLIC HEALTH GENOMICS, 18. p. 12. ISSN 1662-4246

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Abstract

Objective: Introduced by the German as a synthetic opioid analgesic, methadone is used world-wide as a substitution treatment for opioid dependence. It is a chiral compound and its pharmacology is complex. This can further be complicated by population differences in the genetic polymorphisms of enzymes metabolizing the drug and preferential metabolism of specific isomers. Administered as a chiral mixture, its active S-form is preferentially metabolized by the polymorphic CYP2B6, with the CYP2B6*6 allele [SNPs 785A>G (rs2279343) and 516G>T (rs3745274)] associated with slow metabolism. Material and Methods: We genotyped a well-characterized sample of 92 opiate dependent individuals in several prisons in Malaysia and treated with MMT. Daily doses ranged from 5 to 120 mg (mean 57.5±33 mg). Results: Mean S-methadone serum concentrations corrected for dose in subjects homozygous for CYP2B6*6 (4.44±1.87 ng/ml.mg) were significantly higher than for heterozygous (2.64±1.48) and noncarriers (2.70±1.83) (P = 0.046). Similar patterns were observed for R to S-methadone ratios with CYP2B6*6/*6 having lower ratios (0.68±0.10) than heterozygous (1.02±0.39) and non-carriers (1.20±0.67) (P = 0.000). No significant difference was found with R-methadone, the metabolites (EDDP), and the total R,S-methadone serum concentrations. Conclusion: Preferential metabolism of active S-methadone is an important consideration for methadone when interpreting serum concentrations in diverse populations with different patterns of genetic polymorphism of CYP2B6 especially when it is administered as a racemate mixture.

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