氢溴酸樟柳碱注射液大鼠组织分布和Beagle犬药动学研究

目的 研究氢溴酸樟柳碱注射液在大鼠体内的组织分布情况和Beagle犬体内的药动学特征。方法 SD大鼠单次iv氢溴酸樟柳碱注射液5 mg/kg，于给药后5、30、60、90、180 min处死大鼠，取血浆、心、肝、脾、肺、肾、脑、胃、小肠、骨骼肌、脂肪、卵巢、子宫、睾丸。Beagle犬单次iv氢溴酸樟柳碱注射液0.1、0.3、0.9 mg/kg，给药后5、10、20、30、45 min和1.0、1.5、3.0、5.0、7.0、10.0 h静脉采血。采用高效液相色谱-质谱联用法（LC-MS）测定各时间点血浆及各组织中氢溴酸樟柳碱的浓度，统计矩法计算氢溴酸樟柳碱在犬体内的药动学参数。结果 大鼠肾、胃氢溴酸樟柳碱峰浓度最高，分别为（1 967.6±569.4）（2 316.9±952.6） ng/mL，其次为血浆、小肠、肺、肝、脾、卵巢、心、子宫、骨骼肌，而脂肪、睾丸和脑峰浓度最低，低于200 ng/mL。除胃在30 min达峰外，其余组织均在5 min达峰，之后快速下降。Beagle犬iv氢溴酸樟柳碱注射液后，0.1、0.3、0.9 mg/kg组达峰浓度（C_max）分别为（43.3±8.6）、（117.9±40.2）、（348.6±40.0） ng/mL，药时曲线下面积（AUC_0~t）分别为（35.9±6.6）、（159.6±56.6）、（443.3±50.3） ng·h/mL，半衰期（t_1/2z）分别为（0.9±0.3）、（1.5±0.9）、（1.1±0.2）h，清除率（Cl_z）分别为（20.9±5.3）、（17.9±7.6）、（19.4±2.2）×10⁵ L/（h·kg），表观分布容积（V_z）分别为（24.6±7.0）、（37.0±18.5）、（31.3±4.3）×10⁵ L/kg。结论 氢溴酸樟柳碱在大鼠体内的分布与器官血流量、药物水溶性、生理屏障等因素具有明显相关性；在犬体内血浆清除率和组织分布程度均较高，血浆消除较快，无蓄积性。

Studies on tissue distribution of Anisodine Hydrobromide Injection in rats and pharmacokinetics in Beagle dogs

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.