[Association between genetic polymorphisms of CYP2C19 and CYP2C9 and phenytoin serum concentration].
OBJECTIVE
To investigate the relationship between the genetic polymorphism of cytochrome CYP2C19 and CYP2C9 and the serum concentration of phenytoin (PHT) in patients with epilepsy.


METHODS
The peripheral blood samples of 200 patients with epilepsy aged 2 - 68, were collected to undergo PCR. Denaturing high performance liquid chromatography (DHPLC) was used to detect the PCR products so as to examined the 2 common CYP2C19 allele variants and one CYP2C9 allele. The patients were treated with PHT of the dosage of 1.00 - 18.02 mg/kg alone. After 5 half-life periods venous blood was collected before the administration. Fluorescence polarization immunoassay was used to measure the PHT serum concentration standardized by dosage and body weight.


RESULTS
The allele frequencies of CYP2C19 * 2, CYP2C19 * 3, and CYP2C9 * 3 were 31%, 8%, and 6% respectively. Thirty-two patients with CYP2C19 and/or CYP2C9 allele variants were classified into 3 groups: extensive metabolizer (EM, n = 11) homozygous for CYP2C19 * 1/* 1 combined with CYP2C9 * 1/* 1 alleles, intermediate metabolizer (IM, n = 14) heterozygous for CYP2C19 * 1/* 2 or CYP2C19 * 1/* 3 alleles, and poor metabolizer (PM, n = 7) with the genotype of CYP2C19 * 2/* 2 or CP2C19 * 2/* 3, or CYP2C19 * 1/* 2 combined with CYP2C9 * 1/* 3. The genotype distribution rates of EM, IM, and PM were 34%, 44%, and 22% respectively. The PHT serum concentration of the PM group was (4.0 +/- 0.9) Css, significantly higher than that of the IM group [(3.0 +/- 0.9) Css, P < 0.05] and that of the EM group [(2.6 +/- 0.8) Css, P < 0.01] without a significant difference between the IM group and EM group.


CONCLUSIONS
Phenytoin is metabolized via CYP2C19 and CYP2C9. The PHT serum concentration of the PM is significantly higher. Genotyping helps predict the clinical response to PHT administration.
Huang
Yue
Y
Department of Neurobiology, Xuanwu Hospital of Capital University of Medical Sciences, Beijing 100053, China.
Yang
Jing-Fang
JF
Qi
Xiao-Lian
XL
Wang
Yu-Qin
YQ
Wang
Wei-Zhi
WZ
Chen
Biao
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010672:Phenytoin / Q000097:blood* / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D010672:Phenytoin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19