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Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy
Author(s) -
Odani Atsuko,
Hashimoto Yukiya,
Otsuki Yuko,
Uwai Yuichi,
Hattori Haruo,
Furusho Kenshi,
Inui Kenich
Publication year - 1997
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(97)90031-x
Subject(s) - phenytoin , cyp2c9 , epilepsy , pharmacokinetics , allele , cyp2c19 , pharmacology , medicine , polymorphism (computer science) , anticonvulsant , mutation , population , genetics , biology , endocrinology , metabolism , cytochrome p450 , gene , environmental health , psychiatry
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 (Arg 144 →Cys and Ile 359 →Leu) in CYP2C9 and for the defective allele (m1 and m2) in CYP2C19 . 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 CYP2C9 mutation for the Cys 144 allele, whereas six patients were heterozygous for the wild‐type (wt) and Leu 359 allele (wt/Leu 359 ) in CYP2C9 . The maximal elimination rate (V max ) of phenytoin among patients with heterozygous wt/Leu 359 in CYP2C9 was 33% lower than that among patients with normal CYP2C9 . A total of 21 patients were heterozygous for the CYP2C19 mutation (wt/m1 or wt/m2), and five patients had the homozygous or heterozygous mutations in CYP2C19 (m1/m1 or m1/m2). The V max values of phenytoin were slightly decreased (up to 14%) among patients with CYP2C19 mutations compared with patients with normal CYP2C19 . Conclusion 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 (Ile 359 →Leu) is a determinant of impaired metabolism of the drug among Japanese persons. Clinical Pharmacology & Therapeutics (1997) 62 , 287–292; doi: