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

Abstract

Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram ( p = 0.021), and the Treatment Emergent Symptom Scale (TESS) total score ( p = 0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone ( p = 0.035), and showed a lower plasma R-methadone/ methadone dose ratio ( p = 0.007) in urine opiate test negative patients, as well as a greater QTc change ( p = 0.008) and higher total scores of TESS ( p = 0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.

A Possible Mechanistic Link Between the CYP2C19 Genotype, the Methadone Metabolite Ethylidene-1,5-Dimethyl-3,3-Diphenylpyrrolidene (EDDP), and Methadone-Induced Corrected QT Interval Prolongation in a Pilot Study

“…However, a trend was noted (p = 0.1) and is consistent with a previous report associating CYP2C19*2 with change in QTc [23]. Failure to show a direct association between CYP2C19*2 and QTc most probably results from the small sample size.…”

“…CYP3A4 functional variability and variants in the CYP2B6, CYP2D6, CYP2C19, and ABCB1 genes have all been related to broadly disparate metabolism of methadone [19][20][21][22]. Recently, a variant in the CYP2C19 gene was reported to be associated with a QTc change in 366 patients receiving methadone maintenance therapy [23], suggesting broader genetic influences on methadoneassociated QTc prolongation than originally thought. In addition, a common variant at the NOS1AP locus (rs12143842) was found to be associated with a prolonged QT interval in population studies and may contribute to QT prolongation among those on methadone therapy [24,25].…”

Pharmacogenomics study in a Taiwanese methadone maintenance cohort

“…The higher the withdrawal symptoms scores, the higher the side effect symptom score, but the lower the betel nut use. The gene dose of CYP2C19 showed significant associations with methadone dose, R -methadone/methadone dose, and R -EDDP/methadone dose [13]. Gene dose is associated with TESS scores in patients testing positive for urine morphine.…”

“…Selection of SNPs was based on literature reports [2,6,9-13], a minor allele frequency of greater than 0.1 on the HapMap in Chinese ethnic groups (http://hapmap.ncbi.nlm.nih.gov/index.html.en), and possible functionalities predicted by the bioinformatics tool FastSNP [14]. …”

Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response

“…CYP2C19 comprises 16% of the CYP2C subfamily (Gerbal-Chaloin et al, 2001). Particularly interesting are the results of some studies demonstrating that CYP2C19*2 gene variant (associated with a poor metabolizer phenotype in both the Caucasian and Asian populations) produces higher plasma concentrations of EDDP than individuals carrying the wild-type gene (Carlquist et al, 2015;Wang et al, 2013). This variant was associated with a prolongation of the QT interval of the cardiac cycle and may be useful in identifying patients with increased risk (Carlquist et al, 2015).…”