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

Abstract

Objective To investigate the dose-time-toxicity relationship of liver injury in mice induced by multiple dose of Chaiqin Qingning Capsule and Ganmaoling capsule. Methods Three hundred and ten healthy SPF mice were divided into 7 groups randomly, in which 3 groups were low, medium and high dose subgroups of Chaiqin Qingning capsule (50 mice with male and female half in each subgroup). The doses of Chaiqin Qingning capsule subgroups were 1 437.70, 2 300.31 and 3 680.50 mg/kg, which were 1.63, 1.64 and 1.65 times of clinically equivalent dose (ED) respectively. Three groups were low, medium and high dose subgroups of Ganmaoling capsule (50 mice with male and female half in each subgroup). The doses of Ganmaoling capsule subgroups were 1 452.31, 2 251.08 and 3 489.18 mg/kg, which were 1.553, 1.554 and 1.555 times of ED respectively. One group was the normal control group(10 mice, half were male). Each subgroup mice were treated with intragastric administration of the corresponding concentration drug suspension by 0.20 ml per 10 g body weight, and the normal control group mice were treated with intragastric administration of equal volume of distilled water. All mice were treated once daily for 14 days. The general state of mice in each group was observed during the experiment. Ten mice randomly selected on the 1st, 3rd, 7th, 11th and 14th day after multiple administration of the medicine in each subgroup respectively and 10 mice in the normal control group after 14 days multiple administration of distilled water were weighed, and the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB) and total bilirubin (TBil) levels were tested. Then the mice were executed and the organs, i. e., liver, thymus, and spleen were taken to weigh and calculate the organ index. Results The general state of mice in the normal control group, Chaiqin Qingning capsule subgroups and Ganmaoling capsule low dose subgroup were not abnormal during the administration period. Ganmaoling capsule high dose subgroup appeared 8 mice died within 1 day after first administration, the overall mortality rate was 16%. The high dose and medium dose subgroup of mice showed decrease in activities, dietary, water and body weight significantly on 1st to 3rd day. The symptoms gradually disappeared on 4th to 7th day, and the state gradually returned to normal on 8th to 14th day. The difference of serum level of ALT, AST, ALP, ALB, TBil and liver, thymus and spleen organ index of Chaiqin Qingning capsule subgroups and Ganmaoling capsule low dose subgroup on the 1st, 3rd, 7th, 11th and 14th days after multiple administration compared with those of the normal control group were not statistically significant (all P>0.05). The levels of serum ALT, ALP and TBil of Ganmaoling capsule high dose subgroup mice after multiple administration on 1st, 3rd, 7th day and the serum AST of mice on 1st and 3rd day were significantly higher than those in the normal control group (P<0.05, P<0.01). The serum ALB level of Ganmaoling capsule high dose subgroup mice on 3rd, 7th, 11th and 14th day were significantly lower than those in normal control group (P<0.05, P<0.01). The levels of serum ALT, AST, ALP and TBil of Ganmaoling capsule medium dose subgroup mice after multiple administration on 1st and 3rd day were significantly higher than those in the normal control group (P<0.05, P<0.01). The serum ALB level of Ganmaoling capsule medium dose subgroup mice after multiple administration on 3rd and 7th day were significantly lower than those in normal control group (P<0.05, P<0.01). The liver organ index of mice in Ganmaoling capsule high dose subgroup after multiple administration on 1st , 3rd and Ganmaoling capsule medium dose subgroup after multiple administration on 1st day were significantly higher than that in the normal control group (all P<0.01). Conclusions Multiple intragastric administration of Chaiqin Qingning capsule in different doses did not induce significant hepatotoxicity. Multiple intragastric administration of Ganmaoling capsule in medium dose or high dose could induce hepatotoxicity in mice, and showed an obvious dose-time-toxicity relationship. Key words: Drug-induced liver injury; Dose-response relationship, drug; Chaiqin Qingning capsule; Ganmaoling capsule