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 |
Show full item record
CORE Recommender
SCOPUSTM
Citations
147
checked on Sep 30, 2024
Page view(s)
26
checked on Aug 24, 2024
Google ScholarTM
Check
Altmetric
Items in GCRIS Repository are protected by copyright, with all rights reserved, unless otherwise indicated.