Please use this identifier to cite or link to this item: https://hdl.handle.net/11499/5513
Title: The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels
Authors: Kerb, R.
Aynacioglu, A.S.
Brockmöller, J.
Schlagenhaufer, R.
Bauer, S.
Szekeres, T.
Hamwi, A.
Keywords: Pharmacogenetlcs
Polymorphism
TDM
anticonvulsive agent
CYP2C19 protein, human
CYP2C9 protein, human
cytochrome P450
mixed function oxidase
phenytoin
steroid 16alpha monooxygenase
steroid monooxygenase
unspecific monooxygenase
adolescent
adult
aged
analysis of variance
article
blood
chi square distribution
drug monitoring
female
gene
genetic polymorphism
genetics
genotype
human
male
middle aged
prediction and forecasting
statistics
Adolescent
Adult
Aged
Aged, 80 and over
Analysis of Variance
Anticonvulsants
Aryl Hydrocarbon Hydroxylases
Chi-Square Distribution
Cytochrome P-450 Enzyme System
Drug Monitoring
Female
Genes, MDR
Genotype
Humans
Male
Middle Aged
Mixed Function Oxygenases
Phenytoin
Polymorphism, Genetic
Predictive Value of Tests
Steroid 16-alpha-Hydroxylase
Steroid Hydroxylases
Abstract: Phenytoin, an anticonvulsant, exhibits nonlinear pharmacokinetics with large interindividual differences. Because of its small therapeutic range with the risk of therapeutic failure or adverse drug effects in susceptible persons, therapeutic drug monitoring is frequently applied. The interindividual differences in dose response can partially be explained by known genetic polymorphisms in the metabolic enzyme CYP2C9 but a large deal of individual variability remains still unexplained. Part of this variability might be accounted for by variable uptake of phenytoin, which is a substrate of p-glycoprotein, encoded by the human MDR1 gene. We evaluated, whether phenytoin plasma levels correlate with a polymorphism in the MDR1 gene, C3435T, which is associated with intestinal PCP activity. Genotyping and analyses of plasma levels of phenytoin and metabolites in 96 healthy Turkish volunteers showed that the MDR1C > T3435 polymorphism affects phenytoin plasma levels (P = 0.064) and the metabolic ratio of p-HPPH vs phenytoin (MDR1*TT genotype, P = 0.026). The MDR1*CC genotype is more common in volunteers with low phenytoin levels (P ? 0.001, ?2 test). A combined analysis of variable alleles of CYP2C9, 2C19 and MDR1 revealed that the number of mutant CYP2C9 alleles is a major determinant, the number of MDR1*T alleles further contributes to the prediction of phenytoin plasma levels and CYP2C19*2 does not explain individual variability. The regression equation that fitted the data best included the number of mutant CYP2C9 and MDR*T alleles as predictory variables and explained 15.4% of the variability of phenytoin data (r2 = 0.154, P = 0.0002). Furthermore, analysis of CYP2C9 and MDR1 genotypes in 35 phenytoin-treated patients recruited from therapeutic drug monitoring showed that combined CYP2C9 and MDR1 analysis has some predictive value not only in the controlled settings of a clinical trial, but also in the daily clinical practice. © 2001 Nature Publishing Group All rights reserved.
URI: https://hdl.handle.net/11499/5513
https://doi.org/10.1038/sj.tpj.6500025
ISSN: 1470-269X
Appears in Collections:PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Tıp Fakültesi Koleksiyonu

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