Influence of CYP2C9 genetic polymorphism and undernourishment on plasma-free phenytoin concentrations in epileptic patients.
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.
Centre for Advance Research in Pharmacogenomics, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India.
Kesavan
K
Ramasamy
Sunil K
SK
Narayan
Deepak Gopal
DG
Shewade
Adithan
A
Chandrasekaran
D000328:Adult; D000483:Alleles; D000927:Anticonvulsants / Q000097:blood* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004827:Epilepsy / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D044342:Malnutrition / Q000097:blood* / Q000150:complications; D010672:Phenytoin / Q000097:blood* / Q000627:therapeutic use; D011110:Polymorphism, Genetic
D000927:Anticonvulsants; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases