CYP2C19基因型对丙戊酸及其与苯妥英联合用药时血药浓度影响

目的探讨细胞色素P450 2C19(CYP2C19)基因对丙戊酸(VPA)血药浓度,以及VPA和苯妥英(PHT)联合应用时对其VPA血药浓度的影响.方法应用变性高效液相(DHPLC)技术对CYP2C19两个常见的等位基因突变进行了分析;应用荧光偏振免疫法(FPIA)测定口服抗癫痫药物患者的血药浓度.结果81例癫痫患者中CYP2C19外显子4(*3)和外显子5(*2)位点均为野生型(*1/*1)的发生率为37.0%,CYP2C19*2和CYP2C19*3的等位基因频率分别为31.5%和3.7%.单一应用VPA时,弱代谢患者较正常代谢患者的VPA血药浓度有所升高(P＜0.05).联合应用PHT和VPA可使VPA血药浓度显著降低(P＜0.01),CYP2C19正常代谢患者VPA血药浓度降低尤为明显(P＜0.01);在VPA与PHT联合用药过程中,约半数CYP2C19正常代谢患者VPA血药浓度不能达到治疗血药浓度.结论CYP2C19基因多态性影响VPA的血药浓度变化,在联合应用PHT时对VPA血药浓度的影响尤为明显,从而影响抗癫痫的临床疗效.

The Effect of CYP2C19 Genotype on the Csss of Valproate and Valproate Combined with Phenytoin Administration

Objective To investigate the relationship between the genotype of CYP2C19 and the plasma concentrations of valproate (VPA) when it is administrated alone and phenytoin (PHT) combined. Methods Denaturing high performance liquid chromatography (DHPLC) method was used to detect two mutant alleles * 2 and * 3 respectively located on CYP2C19 exonS and exon4. Meanwhile, the method of fluorescence polarization immunoassay (FPIA) was used to detect plasma antiepileptic drugs (AED) concentration of patients. Results The frequency of the CYP2C19 wild genotype was 37. 0% in Chinese patients with epilepsy. The alleles frequencies of CYP2C19 * 2 and * 3 were 31. 5% and 3. 7% respectively. When VPA is administrated alone,the standardized plasma concentration at steady state (Csss) of VPA is higher in poor metabolism patients than that in normal metabolism patients ( P <0. 05). While VPA and PHT were combined administrated, the Csss of VPA decreased significantly ( P <0. 01) comparing with VPA alone. The Csss of VPA in those patients with normal metabolism decreased more markedly than those in poor metabolism patients ( P <0. 01). About half of normal metabolizers could not reach efficacious VPA Csss when VPA and PHT are combined administrated. Conclusions These data suggest that CYP2C19 polymorphism significantly impact the metabolism of VPA particularly in the combined administration with PHT. These findings might have significant implication and guidance for the combined use of AEDs to the patients with refractory epilepsy in clinical practice.