Influence of CYP2C9 Genetic Polymorphism and Undernourishment on Plasma-Free Phenytoin Concentrations in Epileptic Patients
Influence of CYP2C9 Genetic Polymorphism and Undernourishment on Plasma-Free Phenytoin Concentrations in Epileptic Patients
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DOI：
10.1097/ftd.0b013e3181fa97cc
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发表时间：
2010-12-01
影响因子：
2.5
通讯作者：
Chandrasekaran, Adithan
中科院分区：
文献类型：
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作者：
Ramasamy, Kesavan;Narayan, Sunil K.;Chandrasekaran, Adithan
本研究的目的是研究CYP2C9基因多态性和营养不良对癫痫患者体内苯妥英钠游离浓度的影响。这项研究是在70名服用苯妥英钠治疗癫痫发作的患者中进行的。采用聚合酶链式反应-限制性片段长度多态方法检测CYP2C9(*2和*3)基因分型。采用平衡透析法分离苯妥英钠结合血浆和游离苯妥英。用反相高效液相色谱法测定苯妥英钠的总浓度和游离浓度。患者被大致分为营养良好和营养不良两类，并根据CYP2C9基因分型进一步细分。在营养良好组(G1~G3组)中，CYP2C9杂合子(G2)杂合子低代谢组(3.1+/-0.62)和纯合子低代谢(G3)组(4.3+/-1.76)的游离苯妥英钠浓度显著高于野生型(G1)组(1.1+/-0.72 mU/mL)。同样，在营养不良患者组(G4-G6组)中，野生型CYP2C9(G4)组(2.5+/-0.52mU/mL)、杂合型低代谢物(G5)组(4.3+/-1.76 mg/mL)和纯合子低代谢物(G6)组(8.2+/-1.08 mU/mL)的游离苯妥英钠浓度显著高于野生型(G1)组(1.1+/-0.72 mg/mL)。与携带野生型CYP2C9等位基因(G1)的营养不良患者相比，营养不良、CYP2C9等位基因变异和营养不良加等位基因变异患者的游离苯妥英钠浓度分别增加127%、290%和472%。营养不良和遗传因素(CYP2C9等位基因变异)对苯妥英钠毒性的贡献有37.3%的优势比(P<；0.0001)。营养不良和变异的CYP2C9等位基因单独提高游离苯妥英钠浓度，两者结合表现为加性效应。
The objective of this study was to study the effect of CYP2C9 genetic polymorphism and undernourishment on free phenytoin concentrations in epileptic patients. The study was done in 70 patients who were taking phenytoin therapy for the treatment of epileptic seizures. Genotyping of CYP2C9 (*2 and *3) was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Bound and free plasma phenytoin was separated using equilibrium dialysis technique. Total and free phenytoin concentrations were measured by the reverse-phase high-performance liquid chromatography method. Patients were broadly classified into well-nourished and undernourished and further sub-classified by CYP2C9 genotypes. In well-nourished groups (G1 to G3 group), free phenytoin concentrations were significantly higher in the heterozygous poor metabolizer of CYP2C9 genotype (G2) group (3.1 +/- 0.62 mu g/mL) and homozygous poor metabolizer of CYP2C9 genotype (G3) group (4.3 +/- 1.76 mu g/mL) when compared with patients with the wild-type CYP2C9 (G1) group (1.1 +/- 0.72 mu g/mL). Similarly, in undernourished patient groups (G4-G6 group), free phenytoin concentrations were significantly higher in the wild-type CYP2C9 (G4) group (2.5 +/- 0.52 mu g/mL), heterozygous poor metabolizer of CYP2C9 genotype (G5) group (4.3 +/- 1.76 mg/mL), and homozygous poor metabolizer of CYP2C9 genotype (G6) group (8.2 +/- 1.08 mu g/mL) when compared with well-nourished patients with the wild-type CYP2C9 (G1) group (1.1 +/- 0.72 mg/mL). The percentage increase in free phenytoin concentration by undernourishment, CYP2C9 allelic variants, and undernourishment cum CYP2C9 allelic variants were 127%, 290%, and 472%, respectively, compared with well-nourished patients with the wild-type CYP2C9 genotype (G1) group. The contribution of undernourishment and genetic factors (CYP2C9 allelic variant) for developing phenytoin toxicity was calculated to have an odds ratio of 37.3 (P < 0.0001). Undernourishment and variant CYP2C9 alleles elevate free phenytoin concentrations individually and in combination show additive effects.