JOURNAL ARTICLE

[Association between genetic polymorphisms of CYP2C19 and CYP2C9 and phenytoin serum concentration]

Yue Huang, Jing-Fang Yang, Xiao-Lian Qi, Yu-Qin Wang, Wei-Zhi Wang, Biao Chen
Zhonghua Yi Xue za Zhi [Chinese medical journal] 2004 October 17, 84 (20): 1686-9
15569425

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.

CONCLUSION: 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.

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