氯沙坦钾片的生物等效性及CYP2C9*3基因多态性对氯沙坦药代动力学的影响

目的: 评价试验制剂氯沙坦钾片(杭州民生药业)与参比制剂氯沙坦钾片(杭州默沙东制药)的生物等效性及CYP2C9^*3基因多态性对氯沙坦药代动力学的影响。方法: 采用PCR测序法对健康中国汉族受试者CYP2C9^*3(rs1057910 A>C)位点进行基因分型,筛选36名受试者入组本试验,其中CYP2C9^*1/^*1(AA)基因型个体32例,CYP2C9^*1/^*3(AC)基因型个体4例。本研究为两制剂、两周期交叉设计,单次、开放口服给药的单中心试验,给药剂量为氯沙坦钾片(50 mg/片)1片。通过液相色谱-串联质谱法同时测定人血浆中氯沙坦钾及其代谢产物E-3174的浓度,采用DAS3.2.2非房室模型药动学参数计算的方法求算药动学参数。结果: 受试试剂对参比制剂的相对生物利用度分别为氯沙坦(101.5±20.2)%、E-3174(100.0±13.8)%;同CYP2C9^*3为AA基因型受试者相比,AC基因型受试者中氯沙坦的药代动力学参数AUC_0-12、AUC_inf以及C_max升高,其中AUC_0-12、AUC_inf差异有统计学意义;E-3174的药代动力学参数AUC_0-48和AUC_inf降低,不同基因型间差异无统计学意义。结论: 两种制剂生物等效; CYP2C9基因1075A>C突变可导致氯沙坦代谢减慢,但氯沙坦临床剂量可能不需要根据CYP2C9基因型进行调整。

Bioequivalence of losartan potassium tablets and the influence of CYP2C9*3 polymorphism on the metabolism of losartan

AIM: To investigate the bioequivalence between losartan potassium tablets (Hangzhou Minsheng Pharmaceutical Co. Ltd) and losartan potassium tablets (Hangzhou MSD)and the influence of CYP2C9^*3 polymorphism on the metabolism of losartan.METHODS: We genotyped CYP2C9^*3 (rs1057910 A>C) sites of Healthy Chinese Han subjects by direct sequencing of PCR products to identify the distribution of CYP2C9^*3 polymorphism. We enrolled 36 subjects in the trial, among which CYP2C9^*1^*1 (AA) genotype were 32 cases and CYP2C9^*1/^* (AC) genotype were 4 cases. This study was designed to be two formulations, two-period crossover, single, open single-center trial of oral administration, the dose of losartan potassium tablets was 1 (50 mg/tablet). We established an HPLC-MS-MS method for the simultaneous determination of losartan and its metabolite E-3174 in human plasma. The pharmacokinetic parameters were calculated by Non-compartmental model using DAS3.2.2 analysis software.RESULTS: The relative bioavailability of two preparations were(101.5±21.5)% (losartan) and (100.0±13.8) % (E-3174); Compared with the AA genotype, AUC_0-12, AUC_inf and C_max of losartan of the AC genotype subjects were higher, and there had a significant difference of AUC_0-12 and AUC_inf; AUC_0-48 and AUC_inf of E-3174 were lower. There had no significant gene-related difference of AUC_0-48 and AUC_inf.CONCLUSION: The two preparations are bioequivalent. The clinical dosage of losartan may not be adjusted based on genotype in spite of CYP2C9 gene 1075A>C mutation slowing down losartan metabolism.