Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese

Zhou, Qin; Yu, Xianjun; Lin, Hongyu; Wang, L; Qz, Yun; Hu, Songnian; Dm, Wang

doi:10.1038/tpj.2009.31

Cited by 56 publications

(41 citation statements)

References 82 publications

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“…For instance, the frequencies of the loss-of-function genotypes (e.g., in *2 and *3 in CYP2C19) are higher in Asians than Caucasians or Africans (Luo et al, 2006;Mizutani, 2003). In the current study cohort, the frequencies of CYP2C19*2 and *3 were 31.5% and 4.2%, respectively, which were consistent with the report in a previous study in a Han Chinese population (Zhou et al, 2009). The allele frequencies of CYP2C19*17 in Asians were approximately 0.5% (Tsai et al, 2010) to 0.64% (Wang et al, 2009), which were too low to be calculated in our ethnic group.…”

Section: Discussionsupporting

confidence: 91%

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

Wang

Tsou

et al. 2013

OMICS: A Journal of Integrative Biology

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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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Section: Discussionsupporting

confidence: 91%

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

Wang

Tsou

et al. 2013

OMICS: A Journal of Integrative Biology

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“…However, this study also was conducted in small number of subjects (5, 5, and 4 subjects with CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/ *10 genotypes, respectively). Based on our unpublished data, the frequencies of the CYP2D6*wt/*wt, *wt/*10 and *10/*10 genotypes are about 24.7, 43.3 and 25.0 % in the Korean population, respectively, and similar frequencies have been reported in Chinese and Japanese populations (Nishida et al 2000;Ji et al 2002;Zhou et al 2009;Lee et al 2009). Thus, to evaluate the impact of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine, dividing subjects into Fig.…”

Section: Discussionsupporting

confidence: 71%

Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites

Byeon

Kim

et al. 2015

Arch. Pharm. Res.

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To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC-MS/MS. For atomoxetine, the Cmax, AUC0-∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0-∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0-∞ was not different between these groups. The Cmax, AUC0-∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.

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“…Steady-state mean plasma concentration-time profile according to genotypes for SNP rs4918758 after administration of the last dose of indapamide 1.5 mg at 216 h. HOMO homozygous, HET heterozygous, WT wild type, n sample size. Data are mean±SD at specific times of Taiwanese or Chinese, the largest races in Asia (23)(24)(25)(26)(27). The current study provides an extensive survey of the genetic variances among eight selected major DMEs in Taiwanese, which is considered the closest population to Han Chinese.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects

Wang¹,

Hsiong²,

Ho³

et al. 2013

AAPS J

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Abstract. To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25%∼64%), increased area under the plasma level-time curves (30∼76%), increased area under the time infinity (43%∼80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.

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Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese

Cited by 56 publications

References 82 publications

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

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

Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites

Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects

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