Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics

Abstract

Methadone is a synthetic, long-acting opioid with a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. This toxicity can be due in part to the pharmacogenetics of an individual, which influences the pharmacokinetic and pharmacodynamic properties of the drug. Methadone is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, predominately by CYP2B6, followed by CYP3A4, 2C19, 2D6, and to a lesser extent, CYP2C18, 3A7, 2C8, 2C9, 3A5, and 1A2. Single nucleotide polymorphisms (SNPs) located within CYPs have the potential to play an important role in altering methadone metabolism and pharmacodynamics. Several SNPs in the CYP2B6, 3A4, 2C19, 2D6, and 3A5 genes result in increases in methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance. In particular, carriers of CYP2B6*6/*6 may have a greater risk for detrimental adverse effects, as methadone metabolism and clearance are diminished in these individuals. CYP2B6*4, on the other hand, has been observed to decrease plasma concentrations of methadone due to increased methadone clearance. The involvement, contribution, and understanding the role of SNPs in CYP2B6, and other CYP genes, in methadone metabolism can improve the therapeutic uses of methadone in patient outcome and the development of personalized medicine.

Keywords: Cytochrome P450 (CYP); Genetic variant; Methadone metabolism; Pharmacogenetics; Single nucleotide polymorphism (SNP).

Fig. 1.

Eleven methadone metabolites found in human excretion. *Indicates chiral carbon atom. ADH, alcohol dehydrogenase; CYP, cytochrome P450; EDDP, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine; EMDP, 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline; p-HO, para-hydroxy.