Influence of CYP2C9 Genetic Polymorphism and Undernourishment on Plasma-Free Phenytoin Concentrations in Epileptic Patients

Abstract

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.

CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

“…44 Several studies have reported the influence of CYP2C9*2, CYP2C9*3, CYP2C19 *2 and CYP2C19*3 variants on PHT pharmacokinetics. 5,8,9,24,[45][46][47] In contrast, we did not find an association between CYP2C9 (*2, *3) and CYP2C19 (*2, *3) alleles and PHT plasma concentration, supporting the report by Taguchi and colleagues. 10 However, our observation could be owing to the low frequency of these alleles found among MM patients coupled with our small sample size.…”

PharmGKB summary

“…CYP2C9*3 (rs1057910 A > C) is associated with decreased metabolism of phenytoin in vitro and in vivo in pharmacokinetic studies of epileptic patients [4,9,27]. CYP2C9*3 is also associated with increased dose in patients with epilepsy [28].…”

Role of CYP2C9, CYP2C19 and EPHX Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan Caucasian Subjects

“…An A > C transversion at the base pair 1075 in exon 7 (rs 1057910) that results in an isoleucine to leucine change at the codon 359 (Ile359Leu), defines the allelic variant CYP2C9*3 [3,8,9,10,11,12]. On the other hand, the polymorphic isoforms CYP2C19*2 and CYP2C19*3 are caused by a G > A transition at the base pairs 681 in exon 5 (rs 4244285) and 683 in exon 4 (rs 4986893), respectively.…”