CYP2B6SNPs are associated with methadone dose required for effective treatment of opioid addiction

Abstract

Adequate methadone dosing in methadone maintenance treatment (MMT) for opioid addiction is critical for therapeutic success. One of the challenges in dose determination is the inter-individual variability in dose response. Methadone metabolism is attributed primarily to cytochrome P450 enzymes CYP3A4, CYP2B6, and CYP2D6. The CYP2B6*6 allele [SNPs 785A>G (rs2279343) and 516G>T (rs3745274)] was associated with slow methadone metabolism. To explore the effects of CYP2B6*6 allele on methadone dose requirement, it was genotyped in a well-characterized sample of 74 Israeli former heroin addicts in MMT. The sample is primarily of Middle Eastern/European ancestry, based on ancestry informative markers (AIMs). Only patients with no major co-medication that may affect methadone metabolism were included. The stabilizing daily methadone dose in this sample ranges between 13-260 mg (mean 140±52 mg). The mean methadone doses required by subjects homozygous for the variant alleles of the CYP2B6 SNPs 785A>G and 516G>T (88, 96 mg, respectively) were significantly lower than those of the heterozygotes (133, 129 mg, respectively) and the non-carriers (150, 151 mg, respectively) (nominal P = 0.012, 0.048, respectively). The results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T (rs1128503), that was previously shown to be associated with high methadone dose requirement in this population (P = 0.006, 0.030, respectively). An additional 77 CYP2B6, CYP3A4 and CYP2D6 SNPs were genotyped. Of these, 24 SNPs were polymorphic and none showed significant association with methadone dose. Further studies are necessary to replicate these preliminary findings in additional subjects and other populations.

Differences in Methadone Metabolism by CYP2B6 Variants

“…Clinical genetic association studies of methadone plasma concentrations are consistent with diminished methadone N-demethylation by CYP2B6.6 and liver microsomes from CYP2B6*6 carriers. In patients, methadone doses were lower (Hung et al, 2011;Levran et al, 2013), and doseadjusted steady-state S-methadone concentrations were greater (Crettol et al, 2005(Crettol et al, , 2006Eap et al, 2007;Wang et al, 2011) in CYP2B6*6 homozygotes compared with heterozygotes and noncarriers. While these observations suggested that CYP2B6 allelic variants might influence clinical methadone pharmacokinetics, only recently has this been confirmed.…”

“…CYP2B6 polymorphisms may influence clinical methadone disposition. Gene-association studies suggested that the CYP2B6*6 polymorphism was associated with higher dose-adjusted steady-state plasma methadone concentrations (Crettol et al, 2005(Crettol et al, , 2006Eap et al, 2007;Wang et al, 2011) or use of lower methadone doses (Hung et al, 2011;Levran et al, 2013). Formal determination of methadone N-demethylation and clearance showed that both were greater and lesser than wild-types, respectively, in CYP2B6*4 and CYP2B6*6 carriers (Kharasch et al, 2014).…”

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

“…CYP2B6 inhibition by ticlopidine increased methadone enantiomers AUC and reduced methadone N-demethylation and clearance (Kharasch and Stubbert, 2013). Pharmacogenetic studies also evidence CYP2B6 involvement in methadone disposition, with CYP2B6*6/*6 homozygotes having higher dose-adjusted S-methadone plasma concentrations and/or lower dose requirements than heterozygotes or noncarriers (Crettol et al, 2006;Wang et al, 2011;Levran et al, 2013).…”

Methadone’s effect on nAChRs—a link between methadone use and smoking?

“…CYP2B6, rather than CYP3A4, mediates methadone clearance, and CYP2B6 polymorphisms influence plasma concentrations of methadone [102][103][104]. Fast methadone metabolizers may need higher doses of methadone and are thus susceptible to more severe nicotine dependence.…”