Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort.

Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101131135 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-8100 (Electronic) Linking ISSN: 15362310 NLM ISO Abbreviation: OMICS Subsets: MEDLINE

Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., c2002-

Polymorphism, Single Nucleotide*; Aryl Hydrocarbon Hydroxylases/*genetics ; Heart Diseases/*chemically induced ; Heroin Dependence/*drug therapy ; Methadone/*adverse effects; Adult ; Cohort Studies ; Cytochrome P-450 CYP2C19 ; Dose-Response Relationship, Drug ; Female ; Gene Dosage ; Gene Frequency ; Genetic Association Studies ; Heart Diseases/enzymology ; Heart Diseases/genetics ; Heroin Dependence/enzymology ; Heroin Dependence/genetics ; Humans ; Maintenance Chemotherapy ; Male ; Methadone/pharmacokinetics ; Methadone/therapeutic use ; Myocardial Contraction/drug effects ; Opiate Substitution Treatment

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.

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EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
EC 1.14.14.1 (CYP2C19 protein, human)
EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
UC6VBE7V1Z (Methadone)

Date Created: 20130911 Date Completed: 20140417 Latest Revision: 20211021

20240104

PMC3783925

10.1089/omi.2012.0068

24016178