Genetic analysis of the S-mephenytoin polymorphism in a chinese population*

Abstract

The 4'-hydroxylation of S-mephenytoin exhibits a polymorphism in humans, with the poor metabolizer phenotype exhibiting a lower frequency in white (3% to 5%) than in Oriental populations (13% to 23%). Two mutations in CYP2C19 (CYP2C19m1 and CYP2C19m2) have recently been described that account for approximately 85% of white and 100% of Japanese poor metabolizers. This study examines whether these mutations account for the poor metabolizer phenotype in the Chinese population. The metabolism of S-mephenytoin exhibited a bimodal distribution in 244 unrelated Chinese subjects, although the distribution of the two phenotypes overlapped. In 75 selected Chinese subjects, CYP2C19 genotype analysis predicted the phenotype with 100% accuracy. The frequency of the poor metabolizer phenotype was approximately 11% (95% confidence interval 7% to 15%). The frequency of the CYP2C19m1 allele was 0.289, whereas that of CYP2C19m2 was 0.044. Homozygous extensive metabolizers had slightly lower ratios of S/R-mephenytoin compared with heterozygous extensive metabolizers, showing a gene-dosage effect. These data show the advantages of genotype analysis in investigations of the mephenytoin phenotype in Oriental subjects.

Prediction of In Vivo Clearance and Associated Variability of CYP2C19 Substrates by Genotypes in Populations Utilizing a Pharmacogenetics-Based Mechanistic Model

“…Among the three studies without genetic information (populations 1, 13, and 14) (Wedlund et al, 1984;Sanz et al, 1989;Bertilsson et al, 1992), the mean of observed ratios ranged twofold (0.18-0.37), and CV values of the ratios were comparable (96-109%). Among the eight studies or 10 populations (populations 2-8 and 10-12) in which only CYP2C19 null alleles were genotyped (Chang et al, 1995;de Morais et al, 1995;Persson et al, 1996;Goldstein et al, 1997;Xiao et al, 1997;Sviri et al, 1999;Aklillu et al, 2002;He et al, 2002), the mean of observed ratios ranged 1.9-, 1.5-, 1.2-, and 1.3-fold for CYP2C19*1/*1 OR *1/*17 OR *17/*17 (0.13-0.23), *1/null OR *17/null (0.21-0.33), null/null (0.97-1.11), and non-PM (0.21-0.29), respectively. Although CV values of the observed ratios were lowered in comparison with those of the three studies without genetic information, they were still high and varied among studies within each genotype, ranging between 57-79, 36-68, 2-7, and 52-70%, respectively.…”

“…Fourteen populations investigated in 12 clinical studies of mephenytoin (Wedlund et al, 1984;Sanz et al, 1989;Bertilsson et al, 1992;Chang et al, 1995;de Morais et al, 1995;Persson et al, 1996;Goldstein et al, 1997;Xiao et al, 1997;Sviri et al, 1999;Aklillu et al, 2002;He et al, 2002;Sim et al, 2006) were collated from the data published between 1992 and 2006 using the PubMed online database. Selection criteria included the following: 1) healthy normal adult subjects, 2) a single oral administration of 100 mg racemic mephenytoin, and 3) availability of urinary S/R-mephenytoin ratio at 0-8 hours that were either reported or reasonably recovered by digitization of figures.…”

O-Dealkylation of Fluoxetine in Relation toCYP2C19Gene Dose and Involvement of CYP3A4 in Human Liver Microsomes

“…This was probably due to the higher activity of fluoxetine O-dealkylation at a low substrate concentration in the homozygous EMs. In fact, some studies have shown that gene dose has an effect on CYP2C19 activity (homozygous EMs Ͼ heterozygous EMs Ͼ PMs) (de Morais et al, 1995;Shu et al, 2000). As a result, the genotype-related differences in CYP2C19 activity may result in different apparent enzyme kinetics for a metabolic reaction mediated by CYP2C19 and other enzymes between different genotyped liver microsomes.…”

“…Liver donors were genotyped for CYP2C19 from whole blood or liver tissues according to the method of de Morais et al (1995). Of the 34 liver donors, 18 liver microsomes were genotyped as homozygous EMs (wt/wt), 13 heterozygous EMs (wt/m1), and three PMs with the m1 mutation (m1/m1).…”

Influence of CYP2C19 functional polymorphism on Helicobacter pylori eradication

“…A recent meta-analysis showed that the impact of CYP2C19 polymorphism on H. pylori eradication rates appears to be clinically relevant in patients receiving PPI as a component of dual or triple-drug therapy (7). Differences in plasma antibiotics and PPI levels among different CYP2C19 genotype groups result in different cure rates for H. pylori infection among the respective different CYP2C19 genotype groups (15).…”