The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: Studies in stereoselective hydroxylation and population pharmacokinetics
The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: Studies in stereoselective hydroxylation and population pharmacokinetics
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DOI：
10.1111/j.1528-1157.1998.tb01330.x
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发表时间：
1998-12-01
期刊：
影响因子：
5.6
通讯作者：
Tashiro, N
中科院分区：
文献类型：
--
作者：
Mamiya, K;Ieiri, I;Tashiro, N
目的：探讨细胞色素P-450(CYP)2C9和2C19基因多态性对苯妥英(PHT)代谢的影响。方法：检测134例接受PHT治疗的日本成年癫痫患者的CYP2C9(Arg(144)/Cys，Ile(359)/Leu)和CYP2C19(*1，*2或*3)基因频率，并测定其主要代谢产物5-(4-羟基苯基)-5-苯海因(p-HPPH)对映体的血药浓度。结果：等位基因Leu(359)杂合子的平均最大消除速率(V-max)降低了42%，杂合子广泛代谢者和劣代谢者的米氏常数(K-m)分别为22%和54%。(R)-和(S)-p-HPPH/PHT比值在有突变的患者中明显低于无突变的患者。结论：虽然细胞色素P450的羟基化能力随着基因突变的发生而受损，但对细胞色素P450的损伤更大。鉴于PHT的临床应用，从这项人群研究中得出了两个重要结论。首先，即使在较低的日剂量下，携带CYP2C9中Leu(359)等位基因的患者的血清PHT浓度也会急剧上升。其次，携带CYP2C19基因突变的患者应慎重服用较大剂量的PHT。
Purpose: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P-450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.Methods: The genotype of CYP2C9 (Arg(144)/Cys, Ile(359)/Leu) and CYP2C19 (*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data.Results: The mean maximal elimination rate (V-max) was 42% lower in the heterozygote for Leu(359) allele in CYP2C9, and the mean Michaelis-Menten constants (K-m) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)- and (S)-p-HPPH/PHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations.Conclusions: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu(359) allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.