柴芩清宁胶囊与感冒灵胶囊单次给药对小鼠肝毒性的“量-时-毒”关系对比研究被引量：2

Experimental study on the ＂dose-time-toxicity＂ relationship of hepatotoxicity induced by a single-dose of Chaiqin Qingning capsule（柴芩清宁胶囊）and Ganmaoling capsule（感冒灵胶囊） in mice

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摘要目的比较柴芩清宁胶囊和感冒灵胶囊单次给药对小鼠肝毒性的“量-时-毒”关系。方法“时-毒”研究设19组（每组10只小鼠），其中9组为柴芩清宁胶囊组的亚组，9组为感冒灵胶囊组的亚组，柴芩清宁胶囊组小鼠以临床等效剂量（ED）1.6^5倍（相当于70 kg正常成人日剂量的 95.42倍）的该药混悬液单次灌胃，感冒灵胶囊组小鼠以1.55^4 ED（相当于70 kg正常成人日剂量的52.53倍）的该药混悬液单次灌胃，分别分为给药后1 h、2 h、4 h、8 h、12 h、24 h、48 h、72 h和96 h亚组；1组为正常对照组（以蒸馏水灌胃）。“量-毒”研究设13组（每组10只小鼠），其中6组为柴芩清宁胶囊组的亚组，依给药剂量分为ED、1.6ED、1.6^2ED、1.6^3ED、1.6^4ED和1.6^5ED亚组（分别为351.00、561.60、898.56、1 437.70、2 300.31和3 680.50 mg/kg）；6组为感冒灵胶囊组的亚组，依给药剂量分为ED、1.55ED、1.55^2ED、1.55^3ED、1.55^4ED和1.55^5ED亚组（分别为390.00、604.50、936.98、1 452.31、2 251.08和3 489.18 mg/kg）；1组为正常对照组（以蒸馏水灌胃）。“时-毒”研究于设定的给药后不同时间、“量-毒”研究于给药后12 h称量小鼠体重，检测血清ALT、AST、ALP水平，计算肝脏、脾脏和胸腺的脏器指数。结果柴芩清宁胶囊的9个不同时点亚组和6个不同剂量亚组小鼠血清ALT、AST和ALP水平及肝脏、脾脏和胸腺脏器指数与正常对照组比较，差异均无统计学意义（均P＞0.05）。感冒灵胶囊组中的2 h、4 h、8 h、12 h、24 h亚组和1.55^3ED、1.55^4ED 和1.55^5ED亚组小鼠血清ALT、AST、ALP水平，48 h亚组血清ALT水平，1.55^2ED亚组血清ALT、AST水平，以及8 h、12 h亚组和1.55^3ED、1.55^4ED、1.55^5ED亚组小鼠肝脏脏器指数均明显高于正常对照组（P〈0.05，P〈0.01）。“时-毒”研究中以12 h亚组小鼠血清ALT、AST和ALP水平和肝脏脏器指数最高［（1 017.0±342.6）U/L，（281.3±60.1）U/L，（171.8±43.5）U/L，（6.76±0.60）g/100 g］，“量-毒”研究中以1.55^5ED亚组最高［（2 930.6±661.5）U/L，（888.8±180.6）U/L，（392.7±42.4）U/L，（7.21±1.12）g/100 g］。结论柴芩清宁胶囊大剂量单次灌服对小鼠无明显肝毒性。感冒灵胶囊大剂量单次灌服可造成小鼠急性肝损伤，且呈现一定的“量-时-毒”关系。 Objective To compare the ＂dose-time-toxicity＂ relationship of acute liver injury in mice induced by a single-dose of Chaiqin Qingning capsule or Ganmaoling capsule.Methods＂Time-toxicity＂ study： the mice were divided into 19 subgroups （10 mice in each subgroup）, including 9 Chaiqin Qingning capsule subgroups, 9 Ganmaoling capsule subgroups, and 1 normal control group （treated with distilled water）. The mice in the Chaiqin Qingning capsule group were treated with a single intragastric administration with 1.65 times of clinically equivalent dose （ED）（equal to 95.42 times of 70 kg normal adult daily dose） of the drug suspension. The mice in the Ganmaoling capsule group were treated with a single intragastric administration with 1.554 times of ED （equal to 52.53 times of 70 kg normal adult daily dose） of the drug suspension. The mice in the Chaiqin Qingning capsule group and Ganmaoling capsule group were divided into 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h and 96 h subgroups after administration, respectively. ＂Dose-toxicity＂ study： the mice were divided into 13 subgroups （10 mice in each subgroup）, including 6 Chaiqin Qingning capsule subgroups （according to dose, the mice were divided into ED, 1.6ED, 1.6^2ED, 1.6^3ED, 1.6^4ED and 1.6^5ED subgroups; 351.00, 561.60, 898.56, 1 437.70, 2 300.31 and 3 680.50 mg/kg, respectively）, 6 Chaiqin Qingning capsule subgroups （according to dose, the mice were divided into ED, 1.55ED, 1.55^2ED, 1.55^3ED, 1.55^4ED and 1.55^5ED subgroups; 390.00, 604.50, 936.98, 1 452.31, 2 251.08 and 3 489.18 mg/kg, respectively）, and 1 normal control group （treated with distilled water）. ＂Time-toxicity＂ was studied at different times after the drugs administration and ＂dose toxicity＂ was studied at 12 h after administration. General state and body weight of mice were observed. The changes of the levels of ALT, AST, and ALP in serum and organ index of liver, spleen, and thymus were tested.ResultsThe difference of serum levels of ALT, AST, and ALP and liver, spleen, and thymus organ index of mice between the 9 different time subgroups and the 6 different dose subgroups in Chaiqin Qingning capsule group and the normal control group were not statistically significant （all P〉0.05）. The ALT, AST, and ALP levels in the 2 h, 4 h, 8 h, 12 h, and 24 h subgroups and the 1.55^3ED, 1.55^4ED, and 1.55^5ED subgroups, the serum levels of ALT in the 48 h subgroup, the serum levels of ALT and AST in the 1.552ED subgroup, and liver organ index in mice in the 8 h and 12 h subgroups and the 1.55^3ED, 1.55^4ED, 1.55^5ED subgroups in the Ganmaoling capsule group were significantly higher than those in the normal control group （P〈0.05, P〈0.01）. The serum levels of ALT, AST, ALP, and liver organ index in the 12 h subgroup were the highest in the ＂time-toxicity＂ study [（1 017.0±342.6） U/L, （281.3±60.1） U/L, （171.8±43.5） U/L, （6.76±0.60） g/100 g], and the serum levels of ALT, AST, ALP, and liver organ index in the 1.55^5ED subgroup were the highest in the ＂dose-toxicity＂ study [（2 930.6±661.5） U/L, （888.8±180.6） U/L, （392.7±42.4） U/L, （7.21±1.12） g/100 g].ConclusionsA single large dose of Chaiqin Qingning capsule did not induce significant hepatotoxicity in mice. A single large dose of Ganmaoling capsule could induce acute liver injury in mice and showed a significant ＂dose-time-toxicity＂ relationship.

作者安祥高静飞丁选胜

机构地区中国药科大学基础医学与临床药学学院临床药学系精准医学研究室

出处《药物不良反应杂志》 CSCD 2016年第4期249-254,共6页 Adverse Drug Reactions Journal

关键词药物性肝损伤剂量效应关系药物毒性试验小鼠柴芩清宁胶囊感冒灵胶囊 Drug-induced liver injury Dose-response relationship, drug Toxicity tests Mice Chaiqin Qingning capsule Ganmaoling capsule .

分类号 R285.5 [医药卫生—中药学]