地奥司明片在健康人体内的药动学

Pharmacokinetics of diosmin tablets in healthy volunteers

目的：建立人血浆中地奥司明代谢物香叶木素浓度的LC-MS/MS测定法,研究地奥司明片在健康人体内的药动学。方法：采用自身双交叉试验设计,22例中国男性健康受试者,分别单剂量和bid连续7 d多剂量口服地奥司明片900 mg,并于单剂量和多剂量最后一次给药后0-96 h间隔采集静脉血分离血浆样品待测。经β-葡萄糖醛酸酶酶解和甲基叔丁基醚-异丙醇（1∶1）提取处理,LC-MS/MS法测定血浆中香叶木素的浓度,用DAS 2.0软件计算药动学参数。结果：建立的LC-MS/MS法测定血浆香叶木素浓度在0.1-40 ng·mL^-1范围内线性关系良好,最低定量限为0.1 ng·mL^-1,经方法验证符合生物样品测定要求。测得受试者900 mg单剂量和多剂量给药后的主要药动学参数如下：Cmax分别为（4.2±3.8）和（10.3±6.3）ng·mL^-1,Tmax分别为（18.7±9.9）和（6.1±7.0）h,t1/2分别为（60.2±85.7）和（102.5±174.8）h,AUC0-96分别为（185.4±166.2）和（277.6±143.8）h·ng·mL^-1,AUC0-∞分别为（237.2±170.5）和（551.0±606.4）h·ng·mL^-1。结论：建立的LC-MS/MS法专属、灵敏、准确,适用于地奥司明片的药动学研究。

Objective：To establish an LC-MS/MS method for the determination of diosmetin（metabolite of diosmin） in human plasma,and to investigate the pharmacokinetics of diosmin tablets in healthy volunteers.Methods：In a randomized and crossover study,twenty-two male Chinese volunteers were given a single or multiple（bid for seven days） oral dose of 900 mg diosmin tablets after an overnight fast.Then,venous blood was collected at predetermined time points（0 - 96 h）.The plasma samples separated were determined by an established LC-MS /MS method after enzyme hydrolysis with β-glucuronidase and extraction by methyl tertbutyl ether-isopropranol.The pharmacokinetic parameters of diosmetin were calculated by DAS 2.0 software.Results：The established LC-MS /MS method had a linear calibration range over 0.1 - 40 ng·mL^- 1 with an LLOQ of 0.1 ng·mL^- 1 for diosmetin in human plasma.The method validation met the criteria for bio-samples determination.The main pharmacokinetic parameters of diosmin tablets after 900 mg single or multiple oral dose were as follows：Cmax（4.2 ± 3.8） and（10.3 ±6.3） ng·mL^- 1,Tmax（18.7 ±9.9） and（6.1 ±7.0） h,t1 /2（60.2 ±85.7） and（102.5 ±174.8） h,AUC0 ~ 96（185.4 ±166.2） and（277.6 ±143.8） h·ng·mL^- 1,and AUC0 - ∞（237.2 ±170.5） and（551.0 ±606.4） h·ng·mL^- 1.Conclusion：The LC-MS /MS method is proved to be specific,sensitive and accurate,and can be applied in pharmacokinetic study of diosmin tablets.