title: Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort.
abstract: 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.
authors.affiliation: 1 Center for Neuropsychiatric Research, National Health Research Institutes , Miaoli, Taiwan .
authors.forename: Sheng-Chang
authors.initials: SC
authors.lastname: Wang
authors.forename: Ing-Kang
authors.initials: IK
authors.lastname: Ho
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Tsou
authors.forename: Sheng-Wen
authors.initials: SW
authors.lastname: Liu
authors.forename: Chin-Fu
authors.initials: CF
authors.lastname: Hsiao
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Chen
authors.forename: Happy Kuy-Lok
authors.initials: HK
authors.lastname: Tan
authors.forename: Linen
authors.initials: L
authors.lastname: Lin
authors.forename: Chi-Shin
authors.initials: CS
authors.lastname: Wu
authors.forename: Lien-Wen
authors.initials: LW
authors.lastname: Su
authors.forename: Chieh-Liang
authors.initials: CL
authors.lastname: Huang
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Yang
authors.forename: Ming-Lun
authors.initials: ML
authors.lastname: Liu
authors.forename: Keh-Ming
authors.initials: KM
authors.lastname: Lin
authors.forename: Shu Chih
authors.initials: SC
authors.lastname: Liu
authors.forename: Hsiao-Yu
authors.initials: HY
authors.lastname: Wu
authors.forename: Hsiang-Wei
authors.initials: HW
authors.lastname: Kuo
authors.forename: Andrew C H
authors.initials: AC
authors.lastname: Chen
authors.forename: Yao-Sheng
authors.initials: YS
authors.lastname: Chang
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Liu
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D056726:Genetic Association Studies; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D006556:Heroin Dependence / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008691:Methadone / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009200:Myocardial Contraction / Q000187:drug effects; D058850:Opiate Substitution Treatment; D020641:Polymorphism, Single Nucleotide
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008691:Methadone
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