CYP2C19 genotype and S-mephenytoin 4′-hydroxylation phenotype in a Chinese Dai population

He, Nan; Yan, Feng; Huang, Shan-Yan; Wang, Wei; Xiao, Zhousheng; Liu, Zhao‐Qian; Zhou, Hong

doi:10.1007/s00228-002-0425-x

Cited by 42 publications

(28 citation statements)

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“…In analogy to our results, a clear-cut discrimination between CYP2C19*1/*1 homozygote and *1/*2 heterozygote extensive metabolizers was achieved neither with the S/R-Ratio of mephenytoin 33,41 nor with the omeprazole metabolic ratio. 42,43 Similar finding for several metrics indicate that although homozygous extensive metabolizers may have a slightly higher CYP2C19 activity than heterozygous extensive metabolizers, this difference is probably not relevant for any drug metabolized by CYP2C19.…”

Section: ´-Hydroxymephenytoin Metrics For Cyp2c19 Activitysupporting

confidence: 81%

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

Klaassen

Jetter²,

Tomalik-Scharte³

et al. 2007

Eur J Clin Pharmacol

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OBJECTIVES: (S)-Mephenytoin is selectively metabolised to (S)-4'-hydroxymephenytoin by CYP2C19. The urinary excretion of 4'-hydroxymephenytoin reflects the activity of individual enzymes. We evaluated fractioned urinary collection and beta-glucuronidase pre-treatment in order to determine the optimal CYP2C19 metrics. We also assessed whether urinary excretion of N-desmethylmephenytoin (nirvanol) might be a useful CYP2B6 metric in in vivo studies. METHODS: A 50-mg dose of mephenytoin was administered to 52 volunteers as a component of phenotyping cocktails in four separate studies. Urine was collected up to 166 h post-dose. Urinary excretion of 4'-hydroxymephenytoin and nirvanol was quantified by liquid chromatography-tandem mass spectrometry, and common CYP2C19 and CYP2B6 genotypes were determined. RESULTS: Cumulative excretion of 4'-hydroxymephenytoin in urine with beta-glucuronidase treatment collected from before mephenytoin administration up to 12-16 h thereafter showed the greatest difference between CYP2C19 genotypes and the lowest intra-individual variability (7%). Renal elimination of nirvanol was highest for a *4/*4 individual and lowest for individuals carrying the *5/*5 and *1/*7 genotype, but lasted for several weeks, thus making its use in cross-over studies difficult. CONCLUSION: Cumulative urinary excretion of 4'-hydroxymephenytoin 0-12 h post-administration is a sensitive and reproducible metric of CYP2C19 activity, enabling the effect of a drug on CYP2C19 to be assessed in a small sample size of n=6 volunteers. While nirvanol excretion may reflect CYP2B6 activity in vivo, it is not useful for CYP2B6 phenotyping. We evaluated fractioned urinary collection and β-glucuronidase pre-treatment to assess the optimal CYP2C19 metric. Furthermore, we addressed whether urinary excretion of N-desmethylmephenytoin (nirvanol) might be a useful CYP2B6 metric in vivo.Methods: 50 mg of mephenytoin was administered to 52 volunteers as part of phenotyping cocktails in four separate studies. Urine was collected up to 166 hours postdose. Urinary excretion of 4'-hydroxymephenytoin and nirvanol was quantified by LC-MS/MS, and common CYP2C19 and CYP2B6 genotypes were determined.Results: Cumulative excretion of 4'-hydroxymephenytoin in urine with β-glucuronidase treatment collected from before mephenytoin administration up to 12-16 hours thereafter showed the greatest difference between CYP2C19 genotypes and the lowest intraindividual variability (7 %). Renal elimination of nirvanol was highest for a *4/*4 individual and lowest for individuals carrying the *5/*5 and *1/*7 genotype, but lasted for several weeks, thus making its use in cross-over studies difficult. Conclusion:Cumulative urinary excretion of 4'-hydroxymephenytoin 0-12 hours is a sensitive and reproducible metric of CYP2C19 activity, allowing a small sample size of n=6 volunteers to assess the effect of a drug on CYP2C19. While nirvanol excretion may reflect CYP2B6 activity in vivo, it is not useful for CYP2B6 phenotyping.3

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Section: ´-Hydroxymephenytoin Metrics For Cyp2c19 Activitysupporting

confidence: 81%

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

Klaassen

Jetter²,

Tomalik-Scharte³

et al. 2007

Eur J Clin Pharmacol

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Pk Modeling and Simulations Of Urinary S/r-mephenytoin Ratiomentioning

confidence: 99%

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

et al. 2015

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It is important to examine the cytochrome P450 2C19 (CYP2C19) genetic contribution to drug disposition and responses of CYP2C19 substrates during drug development. Design of such clinical trials requires projection of genotype-dependent in vivo clearance and associated variabilities of the investigational drug, which is not generally available during early stages of drug development, but is essential for CYP2C19 substrates with multiple clearance pathways. This study evaluated the utility of pharmacogenetics-based mechanistic modeling in predicting such parameters. Hepatic CYP2C19 activity and variability within genotypes were derived from in vitro S-mephenytoin metabolic activity in genotyped human liver microsomes (N = 128). These data were then used in mechanistic models to predict genotype-dependent disposition of CYP2C19 substrates (i.e., S-mephenytoin, citalopram, pantoprazole, and voriconazole) by incorporating in vivo clearance or pharmacokinetics of wild-type subjects and parameters of other clearance pathways. Relative to the wild-type, the CYP2C19 abundance (coefficient of variation percentage) in CYP2C19*17/*17, *1/*17, *1/*1, *17/null, *1/null, and null/null microsomes was estimated as 1.85 (117%), 1.79 (155%), 1.00 (138%), 0.83 (80%), 0.38 (130%), and 0 (0%), respectively. The subsequent modeling and simulations predicted, within 2-fold of the observed, the means and variabilities of urinary S/R-mephenytoin ratio (36 of 37 genetic groups), the oral clearance of citalopram (9 of 9 genetic groups) and pantoprazole (6 of 6 genetic groups), and voriconazole oral clearance (4 of 4 genetic groups). Thus, relative CYP2C19 genotype-dependent hepatic activity and variability were quantified in vitro and used in a mechanistic model to predict pharmacokinetic variability, thus allowing the design of pharmacogenetics and drug-drug interaction trials for CYP2C19 substrates.

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“…Previous studies carried out by our laboratory have found that interethnic differences with respect to polymorphisms in drug metabolizing enzymes such as CYP2C19 exist between Han and Dai populations. He et al reported that the frequency of the CYP2C19*3 allele in a Dai population was significantly lower than that in a Han population [13] . In the present study, we found that there was no significant difference in the frequencies of the β 1 -adrenoceptor Ser49Gly and Gly389Arg polymorphisms between the two ethnic groups.…”

Section: Discussionmentioning

confidence: 97%

“…The Dai group is the 17-largest ethnic group in China, comprising more than one million people, who live chiefly in the west of Yunnan province, in South-western China [12] . Our previous studies showed that the incidence of drug metabolizing enzyme polymorphisms varies in different ethnic groups [13] . It was therefore interesting to determine whether the incidence of β 1 -adrenoceptor polymorphisms were concordant in 2 different ethnic populations in the same country.…”

Section: Introductionmentioning

confidence: 99%

Distributive characteristics of Ser49Gly and Gly389Arg genetic polymorphisms of beta1-adrenoceptor in Chinese Han and Dai populations1

Liu

Xiang

et al. 2006

Acta Pharmacologica Sinica

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Aim: Genetic polymorphisms causing Ser49Gly and Gly389Arg mutants of β1‐ adrenoceptor may result in significant changes in the function of this receptor. The aim of the present study was to investigate the frequencies of the Ser49Gly and Gly389Arg mutant alleles in healthy Chinese populations and to investigate the differences between 2 Chinese ethnic groups (Han and Dai populations) with respect to the frequencies of these alleles. Methods: A total of 225 Han Chinese and 175 Dai Chinese unrelated healthy volunteers were recruited for this study. Genomic DNA was extracted from peripheral blood leukocytes by using a standard manual chloroform‐phenol extraction. Fragments spanning the 2 polymorphisms were amplified by using polymerase chain reaction with template genomic DNA and relevant primers. The DNA products including the polymorphic loci were subjected to restriction endonuclease digestion with Eco0109I and BcgI. Digested fragments were detected with an ultraviolet detector after electrophoresis (100 V for approximately 1.5 h). Results: The frequencies of the Gly49 and Arg389 alleles were, respectively, 16.2% and 76.4% in the Han population and 14.6% and 75.7% in the Dai population. Conclusion: The polymorphisms causing the Ser49Gly and Gly389Arg mutations of the β1‐adrenoceptor existed in both healthy Han and Dai Chinese populations. The frequencies of the Ser49Gly and Gly389Arg mutant alleles were not significantly different in the Han and Dai populations. However, the frequency of the Gly389 variant seems to be significantly lower in these 2 populations than in an African‐American population.

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CYP2C19 genotype and S-mephenytoin 4′-hydroxylation phenotype in a Chinese Dai population

Cited by 42 publications

References 1 publication

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

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

Distributive characteristics of Ser49Gly and Gly389Arg genetic polymorphisms of beta1-adrenoceptor in Chinese Han and Dai populations1

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