CYP2C19 PM Research Articles

CYP2C19 Genetic Polymorphism in Thai, Burmese and Karen Populations

The genetic polymorphism of CYP2C19 was examined in three Southeast Asian populations. This study was conducted in 774 Thais, 127 Burmeses and 131 Karens. Genomic DNA was extracted from leucocytes and analyzed by the PCR-RFLP technique. Genotype analysis revealed that the allele frequencies of CYP2C19*1, CYP2C19*2 and CYP2C19*3 in the Thais were 0.68, 0.29 and 0.03, respectively, and those of the Burmese population were 0.66, 0.30 and 0.04, respectively. For Karens, the minority ethnic in Mynmar, the allele frequencies of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were 0.71, 0.28 and 0.01, respectively. The prevalence of PM estimated from genotype data among these three ethnic populations were 9.2%, 11.0%, and 8.4%, respectively. The PM phenotype and the frequencies of CYP2C19 defective alleles, particularly CYP2C19*3 among these three Southeast Asian ethnics appeared to be lower than other Asian populations. Lower prevalence of CYP2C19 PM suggests that these ethnics may have different capacity to metabolize drugs that are substrates of CYP2C19. Certain drug dosage regiments should be considered differently for Asian populations.

Effects of combined CYP2C9 and 2C19 polymorphism on the pharmacokinetics of glibenclamide in Chinese subjects

Background Recent in vitro studies showed that both CYP2C9 and 2C19 contributed to the metabolism of glibenclamide (glyburide). This study investigates the relative in vivo contribution of CYP2C9 and 2C19 to glibenclamide pharmacokinetics. Methods Eighteen healthy male Chinese subjects were divided into 3 groups: CYP2C19 EM/CYP2C9*1/*1 (group 1, n=6), CYP2C19 PM/CYP2C9*1/*1 (group 2, n=6), and CYP2C19 EM/CYP2C9*1/*3 (group 3, n=6). Subject received a single oral dose of 5 mg glibenclamide, and multiple blood samples were collected over 12h. Results No significant differences in glibenclamide pharmacokinetics were observed between CYP2C19 EM and PM subjects (group 1 vs 2). However, the plasma glibenclamide concentration was significantly higher in CYP2C9*1/*3 than CYP2C9*1/*1 subjects regardless of CYP2C19 genotype (group 3 vs 1 or 2), and their respective AUC0-∞ were 1.03±0.50, 0.46±0.13 and 0.57±0.11 μg•h/ml (ANOVA, p<0.05), and respective t1/2 were 3.58± 1.25, 2.09± 0.22 and 2.24± 0.27h (ANOVA p<0.05). In addition, 50% of CYP2C9*1/*3 subjects and 17% of CYP2C9*1/*1 subjects developed blood glucose levels below 3 mmol/L and required oral glucose administration. Conclusion CYP2C9 but not 2C19 polymorphism appears to exert dominant influence on glibenclamide metabolism. In CYP2C9*1/*3 heterozygote subjects, the pharmacokinetics and pharmacodynamics of glibenclamide were markedly changed, and the glibenclamide dosage may need to be adjusted to reduce the risk of hypoglycemia. Clinical Pharmacology & Therapeutics (2005) 77, P23–P23; doi: 10.1016/j.clpt.2004.11.087

Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers.

In-vitro data indicated a contribution of cytochrome P450 enzymes 1A2, 3A4, 2C9, 2C19 and 2D6 to biotransformation of doxepin. We studied the effects of genetic polymorphisms in CYP2D6, CYP2C9 and CYP2C19 on E- and Z-doxepin pharmacokinetics in humans. Doxepin kinetics was studied after a single oral dose of 75 mg in healthy volunteers genotyped as extensive (EM), intermediate (IM) and poor (PM) metabolizers of substrates of CYP2D6 and of CYP2C19 and as slow metabolizers with the CYP2C9 genotype *3/*3. E-, Z-doxepin and -desmethyldoxepin were quantified in plasma by HPLC. Data were analyzed by non-parametric pharmacokinetics and statistics and by population pharmacokinetic modeling considering effects of genotype on clearance and bioavailability. Mean E-doxepin clearance (95% confidence interval) was 406 (390-445), 247 (241-271), and 127 (124-139) l h(-1) in EMs, IMs and PMs of CYP2D6. In addition, EMs had about 2-fold lower bioavailability compared with PMs indicating significant contribution of CYP2D6 to E-doxepin first-pass metabolism. E-doxepin oral clearance was also significantly lower in carriers of CYP2C9*3/*3 (238 l h(-1) ). CYP2C19 was involved in Z-doxepin metabolism with 2.5-fold differences in oral clearances (73 l h(-1) in CYP2C19 PMs compared with 191 l h(-1) in EMs). The area under the curve (0-48 h) of the active metabolite -desmethyldoxepin was dependent on CYP2D6 genotype with a median of 5.28, 1.35, and 1.28 nmol l h(-1) in PMs, IMs, and EMs of CYP2D6. The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans. The CYP2D6 polymorphism had a major impact on E-doxepin pharmacokinetics and CYP2D6 PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses.