阿雷地平肠溶胶囊在中国健康人体内的药代动力学研究

目的:研究中国健康受试者单次和多次口服阿雷地平(AR)肠溶胶囊后阿雷地平(AR)及其主要代谢产物羟基阿雷地平(AR-M1)的药代动力学特征。方法:36名健康受试者,随机分为3组,平行单次口服5,10和20 mg阿雷地平肠溶胶囊的药代动力学研究,10 mg组受试者继续进行多次口服10 mg,qd,连续7 d的药代动力学研究,采用LC-MS/MS法测定血浆中阿雷地平及其主要代谢产物AR-M1的药物浓度,采用DAS 2.1.1软件计算药代动力学参数。结果:单次口服阿雷地平肠溶胶囊5～20 mg后阿雷地平和AR-M1的消除半衰期(t1/2z)分别约为2.0～2.7 h和3.9～5.6 h;达峰浓度(Cmax)随剂量增加呈线性增加,分别为[(2.12±1.14)～(11.34±5.98)μg.L-1]和[(29.41±9.80)～(111.74±24.03)μg.L-1];血药浓度-时间曲线下面积(AUC)也随剂量增加呈线性增加,阿雷地平和AR-M1的AUC0～t分别为[(6.02±2.96)～(30.33±8.88)μg.h.L-1]和[(156.05±32.24)～(776.00±160.47)μg.h.L-1],AUC0～∞分别为[(6.12±2.98)～(30.53±8.89)μg.h.L-1]和[(159.39±33.23)～(785.53±161.92)μg.h.L-1]。多次口服阿雷地平肠溶胶囊10 mg后阿雷地平和AR-M1的t1/2z分别约为2.5和5.5 h,AUC0～t分别为(18.09±5.42)和(604.46±159.66)μg.h.L-1,AUC0～∞分别为(18.25±5.42)和(611.93±162.81)μg.h.L-1。结论:在5～20 mg剂量范围内阿雷地平和AR-M1呈线性药代动力学特征,10 mg多次给药,阿雷地平和AR-M1的Cmax和AUC均较单次给药显著增加,但未见明显蓄积。

Pharmacokinetics of aranidipine enteric capsules in healthy Chinese volunteers

Objective: To determine the pharmacokinetic(PK) characteristics of aranidipine(AR) and its active metabolite hydroxyl-aranidipine(AR-M1) after single and multiple doses of AR enteric capsules in healthy Chinese volunteers.Methods: Totally 36 subjects were randomly assigned to receive AR 5,10 or 20 mg once for the single dose study.In addition,the subjects in 10 mg group received 10 mg,qd for another 7 days for a multiple dose study.The plasma concentrations of AR and AR-M1 were determined by LC-MS/MS,and the parameters were calculated using DAS 2.1.1 software.Results: The elimination half-life(t1/2z) of AR and AR-M1 after po AR 5~20 mg were about 2.0~2.7 h and 3.9~5.6 h.Cmax of AR and AR-M1 increased linearly from(2.12±1.14) to(11.34±5.98) μg·L-1 and(29.41±9.80) to(111.74±24.03) μg·L-1 with the increasing dose.AUC also increased linearly within the dose range of 5~20 mg.AUC0~t of AR and AR-M1 were [(6.02±2.96) to(30.33±8.88) μg·h·L-1] and [(156.05±32.24) to(776.00±160.47) μg·h·L-1],and AUC0~∞ were [(6.12±2.98) to(30.53±8.89) μg·h·L-1] and [(159.39±33.23) to(785.53±161.92) μg·h·L-1],respectively.The pharmacokinetic parameters of AR and AR-M1 in AR 10 mg multiple doses study were as follows: t1/2z about 2.5 and 5.5 h,AUC0~t(18.09±5.42) and(604.46±159.66) μg·h·L-1,AUC0~∞(18.25±5.42) and(611.93±162.81) μg·h·L-1,respectively.Conclusion: AR and AR-M1 exhibit linear pharmacokinetic profiles in AR dose range from 5 to 20 mg.The Cmax and AUC of multiple-dose regimen are significantly increased compared with the single dose regimen.The accumulation of AR and AR-M1 is not significant.