Centre for Advance Research in Pharmacogenomics, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India.
Ther Drug Monit. 2010 Dec;32(6):762-6. doi: 10.1097/FTD.0b013e3181fa97cc.
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 subclassified 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 μg/mL) and homozygous poor metabolizer of CYP2C9 genotype (G3) group (4.3 ± 1.76 μg/mL) when compared with patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/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 μg/mL), heterozygous poor metabolizer of CYP2C9 genotype (G5) group (4.3 ± 1.76 μg/mL), and homozygous poor metabolizer of CYP2C9 genotype (G6) group (8.2 ± 1.08 μg/mL) when compared with well-nourished patients with the wild-type CYP2C9 (G1) group (1.1 ± 0.72 μg/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.
本研究旨在探讨 CYP2C9 基因多态性和营养不良对癫痫患者游离苯妥英浓度的影响。研究纳入 70 例接受苯妥英治疗的癫痫患者。采用聚合酶链反应-限制性片段长度多态性方法检测 CYP2C9(*2 和 *3)基因型。采用平衡透析技术分离结合型和游离型血浆苯妥英。采用反相高效液相色谱法测定总苯妥英和游离苯妥英浓度。根据患者的营养状况（营养良好和营养不良）和 CYP2C9 基因型进行广泛分类，并进一步细分。在营养良好组（G1 至 G3 组）中，CYP2C9 基因型为杂合型弱代谢者（G2）组（3.1±0.62μg/mL）和纯合型弱代谢者（G3）组（4.3±1.76μg/mL）的游离苯妥英浓度明显高于野生型 CYP2C9（G1）组（1.1±0.72μg/mL）。同样，在营养不良患者组（G4-G6 组）中，野生型 CYP2C9（G4）组（2.5±0.52μg/mL）、杂合型弱代谢者 CYP2C9 基因型（G5）组（4.3±1.76μg/mL）和纯合型弱代谢者 CYP2C9 基因型（G6）组（8.2±1.08μg/mL）的游离苯妥英浓度明显高于营养良好的野生型 CYP2C9（G1）组（1.1±0.72μg/mL）。与营养良好的野生型 CYP2C9 基因型（G1）组相比，营养不良、CYP2C9 等位基因变异和营养不良加 CYP2C9 等位基因变异分别使游离苯妥英浓度增加 127%、290%和 472%。营养不良和遗传因素（CYP2C9 等位基因变异）导致苯妥英毒性的发生的比值比计算为 37.3（P<0.0001）。营养不良和变异 CYP2C9 等位基因单独升高游离苯妥英浓度，联合升高显示相加效应。
