高脂饮食对阿雷地平及其活性代谢产物的人体药动学、药效学特征及安全性的影响  

Effects of High-Fat Meal on the Pharmacokinetic and Pharmacodynamic Properties and Safety Profile of Aranidipine Enteric-Coated Capsule in Healthy Chinese Subjects

作　　者：杜海燕[1] 刘文芳[1] 杨跃汉 李静[1] 杨克旭[1] 林阳[1] 吴学思[1] 揭秉章[1] 方珊娟[1] 闫秀娟[1] 贾小欣[1] 周子杰[1] 吴伟[1] 所伟[1] 赵桂平[1] 

机构地区：[1]首都医科大学附属北京安贞医院I期药物临床试验研究室,北京100029 [2]江苏德源药业有限公司,江苏连云港222407

出　　处：《中国药学杂志》2011年第12期948-952,共5页Chinese Pharmaceutical Journal

摘　　要：目的评价高脂饮食对口服阿雷地平肠溶胶囊后健康中国人体内阿雷地平(AR)及其活性代谢产物羟基阿雷地平(AR-M1)的药动学(PK)、药效学(PD)的影响,并评价高脂饮食对该制剂的安全性的影响。方法采用随机、开放、自身交叉试验设计,12名健康受试者(男女各半)分两个阶段分别进行空腹和高脂餐后单次口服AR肠溶胶囊10 mg的PK试验,两次给药间隔7 d。每次给药前及给药后36 h内采集PK血样,采用液相色谱-串联质谱联用法(LC-MS/MS)测定健康受试者给药后血浆中AR及AR-M1的浓度。采用DAS2.1.1软件计算AR和AR-M1的主要PK参数(AUC0-t、AUC0-∞、mρax、tm ax、t1/2、Ke、CL/F、Vd/F等)。给药前及给药后36 h内分别测量收缩压(SBP)、舒张压(DBP)及心率作为药效学指标。整个试验过程中进行全面安全性评估。结果空腹和高脂餐后单次口服AR肠溶胶囊10 mg后,AR的AUC0-t、AUC0-∞、和tm ax有显著性差异(P<0.05)。AR-M1的tm ax有极显著性差异(P<0.01)。其他参数无显著性差异(P>0.05)。空腹和高脂餐后单次口服AR,受试者DBP、SBP发生不同程度降低,其中在给药后8 h两组受试者DBP均显著低于基线值(P<0.05),部分受试者心率加快,但无统计学差异;空腹及高脂餐后两组比较,受试者DBP、SBP及心率均无显著性差异。在空腹和高脂餐后给药,男女受试者的主要药动学参数及各药效学指标均无显著性别差异(P>0.05)。结论高脂饮食导致AR的吸收出现延迟现象,吸收程度显著增加;AR-M1的体内生成延迟;血压、心率无显著变化;本研究制剂安全性较好,试验过程无严重不良事件发生。综合考虑,临床应用不需调整用法用量,但应充分考虑病人的饮食习惯,建议空腹给药及清淡饮食。OBJECTIVE To assess the effects of high-fat meal on the pharmacokinetic（PK） and pharmacodynamic（PD） properties and safety profile of aranidipine（AR） and its active metabolite, hydroxyl-aranidipine （AR-M1）, in health Chinese subjects. METHODS One single-dose, open-label, randomized, crossover study of oral aranidipine enteric-coated capsule was conducted in healthy Chinese subjects. Twelve healthy nonsmoking subjects（6 males, 6 females） aged from 18 to 45 years were orally administrated aranidipine enteric-coated capsule 10 mg in fasted state. After a washout period of 1 week, the subjects were orally administrated aranidipine enteric-coated capsule 10 mg after high-fat breakfast. Plasma samples were collected previous to the administration as well as at indicated time points after the administration. Concentrations of AR and AR-M1 in plasma were determined by HPLC-MS/MS. PK pa- rameters（ AUC0-t, AUC0-∞ , Pmax ,tmax, t1/2, Ke, CL/F, Vd/F, etc. ） of AR and AR-MI were calculated with DAS 2. h 1. Systolic and diastolic blood pressure（ SBP and DBP） and heart rate（HR） were measured before and at indicated time points after the administration. Safety profile assessment was performed throughout the experiment. RESULTS There was significant increase in AUC0-t, AUC0-∞, and tmax for AR given after high-fat meal compared with those in fasted condition （P 〈 0. 05 ）. For AR-M1, there was extremely significant increase in tmax （P 〈 0. 01 ） under high-fat meal condition and no significant difference in other parameters （P 〉 0. 05 ）.There were no significant changes in BP and HR after the administration in a high-fat meal state compared with that in fasted state. Compared with baseline, there was significant decrease in DBP at 8 h after the administration in both fasted and high-fat meal state （ P 〈 0. 05 ）. CONCLUSION Oral administration of aranidipine enteric-coated capsule after high-fat meal results in slow absorption and significant increase in bioavailability of AR

关 键 词：阿雷地平 羟基阿雷地平 高脂饮食 药动学 药效学 安全性 

分 类 号：R965[医药卫生—药理学]