目的 研究氫溴酸樟柳堿注射液在大鼠體內(nèi)的組織分布情況和Beagle犬體內(nèi)的藥動(dòng)學(xué)特征。方法 SD大鼠單次iv氫溴酸樟柳堿注射液5 mg/kg，于給藥后5、30、60、90、180 min處死大鼠，取血漿、心、肝、脾、肺、腎、腦、胃、小腸、骨骼肌、脂肪、卵巢、子宮、睪丸。Beagle犬單次iv氫溴酸樟柳堿注射液0.1、0.3、0.9 mg/kg，給藥后5、10、20、30、45 min和1.0、1.5、3.0、5.0、7.0、10.0 h靜脈采血。采用高效液相色譜-質(zhì)譜聯(lián)用法（LC-MS）測(cè)定各時(shí)間點(diǎn)血漿及各組織中氫溴酸樟柳堿的濃度，統(tǒng)計(jì)矩法計(jì)算氫溴酸樟柳堿在犬體內(nèi)的藥動(dòng)學(xué)參數(shù)。結(jié)果 大鼠腎、胃氫溴酸樟柳堿峰濃度最高，分別為（1 967.6±569.4）（2 316.9±952.6） ng/mL，其次為血漿、小腸、肺、肝、脾、卵巢、心、子宮、骨骼肌，而脂肪、睪丸和腦峰濃度最低，低于200 ng/mL。除胃在30 min達(dá)峰外，其余組織均在5 min達(dá)峰，之后快速下降。Beagle犬iv氫溴酸樟柳堿注射液后，0.1、0.3、0.9 mg/kg組達(dá)峰濃度（C_max）分別為（43.3±8.6）、（117.9±40.2）、（348.6±40.0） ng/mL，藥時(shí)曲線下面積（AUC_0~t）分別為（35.9±6.6）、（159.6±56.6）、（443.3±50.3） ng·h/mL，半衰期（t_1/2z）分別為（0.9±0.3）、（1.5±0.9）、（1.1±0.2）h，清除率（Cl_z）分別為（20.9±5.3）、（17.9±7.6）、（19.4±2.2）×10⁵ L/（h·kg），表觀分布容積（V_z）分別為（24.6±7.0）、（37.0±18.5）、（31.3±4.3）×10⁵ L/kg。結(jié)論 氫溴酸樟柳堿在大鼠體內(nèi)的分布與器官血流量、藥物水溶性、生理屏障等因素具有明顯相關(guān)性；在犬體內(nèi)血漿清除率和組織分布程度均較高，血漿消除較快，無(wú)蓄積性。

Objective To study the tissue distribution of Anisodine Hydrobromide Injection in rats and the pharmacokinetic characteristics in Beagle dogs. Methods SD rats were given a single iv injection of Anisodine Hydrobromide Injection at a dose of 5 mg/kg. Rats were sacrificed at different time points, plasma, heart, liver, spleen, lung, kidney, brain, stomach, small intestine, skeletal muscle, fat, ovary, uterus and testis were collected. Beagle dogs were given a single iv injection of Anisodine Hydrobromide Injection at the dose of 0.1, 0.3, and 0.9 mg/kg, 5, 10, 20, 30, 45 min and 1, 1.5, 3, 5, 7, 10 h after administration blood was collected from cephalic vein. The concentration of anisodine hydrobromide in plasma and tissues at each time point was determined by high performance liquid chromatography-mass spectrometry (LC-MS), and statistical moment method was used to calculate the pharmacokinetic parameters of anisodine hydrobromide in dogs. Results After a single iv injection of Anisodine Hydrobromide Injection in rats, the peak concentrations in kidney, stomach were the highest, respectively (1 967.6 ±569.4) and (2 316.9 ±952.6) ng/mL, followed by plasma, small intestine, lung, liver, spleen, ovary, heart, uterus and skeletal muscle, while the peak concentrations in fat, testis and brain were the lowest, lower than 200 ng/mL. Except for the stomach, the peak was reached in 30 min, and the other tissues reached the peak in 5 min and then declined rapidly. After iv injection of Anisodine Hydrobromide Injection in Beagle dogs, the C_max of each dose group was (43.3 ±8.6), (117.9 ±40.2), and (348.6 ±40.0) ng/mL. AUC_0-t was (35.9 ±6.6), (159.6 ±56.6) and (443.3 ±50.3) ng·h/mL, t_1/2z was (0.9 ±0.3), (1.5 ±0.9), and (1.1 ±0.2) h, Cl_z was (20.9 ±5.3), (17.9 ±7.6), and (19.4 ±2.2)×10⁵ L/(h·kg) and V_z was (24.6 ±7.0), (37.0 ±18.5), and (31.3 ±4.3)×10⁵ L/kg, respectively. Conclusion After iv injection of Anisodine Hydrobromide Injection, its distribution in rats had obvious correlation with organ blood flow, drug water solubility, physiological barrier and other factors. The plasma clearance rate and tissue distribution of anisodine hydrobromide in dogs were high, plasma elimination was fast and there was no accumulation.

R969.1

四川省科技支撐項(xiàng)目（2016sz0027）