Kerb R, Aynacioglu A S, Brockmöller J, Schlagenhaufer R, Bauer S, Szekeres T, Hamwi A, Fritzer-Szekeres M, Baumgartner C, Ongen H Z, Güzelbey P, Roots I, Brinkmann U
Epidauros Biotechnology AG, Pharmacogenetics Laboratory, Bernried, Germany.
Pharmacogenomics J. 2001;1(3):204-10. doi: 10.1038/sj.tpj.6500025.
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 PGP 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 (MDR1TT genotype, P = 0.026). The MDR1CC genotype is more common in volunteers with low phenytoin levels (P < or = 0.001, chi2 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 MDR1T alleles further contributes to the prediction of phenytoin plasma levels and CYP2C192 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.
苯妥英钠是一种抗惊厥药，具有非线性药代动力学，个体间差异较大。由于其治疗窗较窄，易感人群有治疗失败或药物不良反应的风险，因此经常进行治疗药物监测。剂量反应的个体间差异部分可由代谢酶CYP2C9中已知的基因多态性解释，但仍有很大一部分个体变异性无法解释。这种变异性的一部分可能是由于苯妥英钠的可变摄取所致，苯妥英钠是由人类MDR1基因编码的P-糖蛋白的底物。我们评估了苯妥英钠血浆水平是否与MDR1基因的C3435T多态性相关，该多态性与肠道PGP活性有关。对96名健康土耳其志愿者进行基因分型以及苯妥英钠和代谢物血浆水平分析，结果显示MDR1C>T3435多态性影响苯妥英钠血浆水平（P=0.064）以及对羟基苯妥英与苯妥英钠的代谢比（MDR1TT基因型，P=0.026）。MDR1CC基因型在苯妥英钠水平较低的志愿者中更为常见（P≤0.001，卡方检验）。对CYP2C9、2C19和MDR1可变等位基因的联合分析表明，突变型CYP2C9等位基因数量是主要决定因素，MDR1T等位基因数量进一步有助于预测苯妥英钠血浆水平，而CYP2C192无法解释个体变异性。最符合数据的回归方程将突变型CYP2C9和MDR*T等位基因数量作为预测变量，解释了苯妥英钠数据变异性的15.4%（r2=0.154，P=0.0002）。此外，对从治疗药物监测中招募的35名接受苯妥英钠治疗的患者进行CYP2C9和MDR1基因型分析表明，CYP2C9和MDR1联合分析不仅在临床试验的对照环境中具有一定的预测价值，在日常临床实践中也有一定价值。
