Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy.
OBJECTIVE
To examine the genetic polymorphism of CYP2C9 and CYP2C19 and its effect on the pharmacokinetics of phenytoin among 44 Japanese patients with epilepsy.


METHODS
Polymerase chain reaction tests with leukocyte deoxyribonucleic acid were used to detect the mutations for the amino acid substitution (Arg144-->Cys and Ile359-->Leu) in CgammaP2C9 and for the defective allele (m1 and m2) in CgammaP2C19. The pharmacokinetic parameters of phenytoin in individual patients were estimated by means of empirical bayesian analysis, in which the prior information was the population parameters for Japanese patients with epilepsy.


RESULTS
Of the 44 patients, none had the CgammaP2C9 mutation for the Cys144 allele, whereas six patients were heterozygous for the wild-type (wt) and Leu359 allele (wt/Leu359) in cgammaP2C9. The maximal elimination rate (Vmax) of phenytoin among patients with heterozygous wt/Leu359 in CgammaP2C9 was 33% lower than that among patients with normal CgammaP2C9. A total of 21 patients were heterozygous for the CgammaP2C19 mutation (wt/m1 or wt/m2), and five patients had the homozygous or heterozygous mutations in CgammaP2C19 (m1/m1 or m1/m2). The Vmax values of phenytoin were slightly decreased (up to 14%) among patients with CgammaP2C19 mutations compared with patients with normal CgammaP2C19.


CONCLUSIONS
The findings indicated that the genetic polymorphisms of CYP2C isozymes play an important role in the pharmacokinetic variability of phenytoin and that the mutation in CYP2C9 proteins (Ile359-->Leu) is a determinant of impaired metabolism of the drug among Japanese persons.
Odani
A
A
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Hashimoto
Y
Y
Otsuki
Y
Y
Uwai
Y
Y
Hattori
H
H
Furusho
K
K
Inui
K
K
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000737:chemistry / Q000235:genetics*
D000927:Anticonvulsants; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D039181:Steroid 16-alpha-Hydroxylase