枸橼酸莫沙必利注射液促小鼠胃肠动力作用及大鼠药代动力学研究

Effect of Mosapride Citrate on Gastrointestinal Motility in Mice and Pharmacokinetics in Rats

目的:研究枸橼酸莫沙必利注射液对小鼠胃肠动力的促进作用以及药代动力学特点,并与口服制剂进行比较,为注射制剂的开发提供科学依据。方法:正常小鼠胃肠动力实验分为正常组、溶媒组、两个注射剂量组(0.1、0.2 mg/kg)和两个灌胃剂量组(1、2 mg/kg);阿托品致胃肠动力障碍小鼠试验分为正常组、模型组、溶媒组、三个剂量注射组(0.015、0.05、0.15 mg/kg)和一个灌胃组(2 mg/kg)。正常和胃肠动力障碍试验各组小鼠给药后30 min灌胃活性炭混悬液,再过30 min后通过测量小肠总长度和碳末在肠内推进距离,计算小肠推进百分比(%);再剪下胃,称胃全质量和胃净质量,计算胃内残留率。药代动力学试验,20只雄性SD大鼠随机分为三个剂量注射组(0.25、0.75、2.5 mg/kg)和一个灌胃组(2.5 mg/kg)。注射组分别在给药前和给药后2 min、10 min、30 min、1 h、2 h、3 h、6 h、12 h采集血液,灌胃组分别在给药前和给药后5 min、15 min、30 min、1 h、2 h、3 h、6 h、12 h采集血液,离心分离血浆,UPLC-MS/MS法测定血浆内莫沙必利的含量。结果:正常小鼠胃肠动力试验中,静脉注射0.1、0.2 mg/kg剂量的枸橼酸莫沙必利,在提高小肠推进率、降低胃内残留方面的作用效果与灌胃1、2 mg/kg剂量相当。胃肠动力障碍小鼠试验中,静脉注射0.015 mg/kg剂量,作用效果与灌胃2 mg/kg剂量相当,并且随着注射剂量的增加,提高小肠推进率和降低胃内残留的作用越显著。药代动力学结果显示,大鼠静脉注射0.25、0.75、2.5 mg/kg剂量和灌胃2.5 mg/kg剂量的枸橼酸莫沙必利,血浆内枸橼酸莫沙必利的AUC_((0-t))分别为57.7、152、541和32.2 μg·L^(-1)·h^(-1),C_(max)分别为183、448、1 621和12.0 μg/L。静脉注射组的C_(max)、AUC_((0-t))均呈剂量相关线性增加,灌胃组暴露量与静脉低剂量相当,最高血药浓度远低于静脉注射低剂量组,生物利用度为4.45%。结论:静脉注射枸橼酸莫沙必利能达到十至百倍剂量灌胃给药方式的作用效果,与口服给药相比具有起效剂量低,起效快等特点,具有一定的临床开发价值。

Objective:To study the promoting effect of mosapride citrate injection on gastrointestinal motility in mice and its pharmacokinetic characteristics in rats,and compare with oral preparation,so as to provide scientific basis for the development of injection preparation.Methods:The gastrointestinal dynamic test of normal mice were divided into normal group,solvent group,two dose injection groups (0.1,0.2 mg/kg) and two intragastric administration groups (1,2 mg/kg).Atropine induced gastrointestinal motility disorder mice were divided into normal group,model group,solvent group,three dose injection groups (0.015,0.05,0.15 mg/kg) and intragastric administration group (2 mg/kg).Animals in each group were given carbon suspension 30 minutes after administration of corresponding solvent or drug,and the percentage (%) of small intestine propulsion was calculated by measuring the total length of small intestine and the distance of carbon particles advancing in intestine after 30 minutes,then cut the stomach,weighed the total weight and the net weight of the stomach,and calculated the residual rate in the stomach.In pharmacokinetic study,20 male SD rats were randomly divided into three dose injection groups (0.25,0.75,2.5 mg/kg) and one intragastric administration group (2.5 mg/kg).Blood samples were collected before and at 2 min,10 min,30 min,1 h,2 h,3 h,6 h,12 h after administration in the injection group,and before and at 5 min,15 min,30 min,1 h,2 h,3 h,6 h,12 h after administration in the intragastric administration group.Plasma was separated by centrifugation,and the contents of mosapride in plasma were determined.Results:In gastrointestinal motility test of normal mice,intravenous administration of mosapride citrate at the dose of 0.1 and 0.2 mg/kg has the same effect on the improvement of small intestine propulsion rate and reduction of gastric residual as intragastric administration at the dose of 1 and 2 mg/kg.In the experiment of gastrointestinal motility disorder mice,the effect of intravenous injection of 0.015 mg/kg was equivalent to that of 2 mg/kg intragastric administration,and with the increase of injection dose,the effect of improving small intestine propulsion rate and reducing gastric residual was more significant.The results of pharmacokinetics showed that after intravenous injection of 0.25,0.75,2.5 mg/kg and oral administation 2.5 mg/kg of mosapride citrate,the AUC_((0-t)) of mosapride in plasma was 57.7,152,541 and 32.2 μg·L^(-1)·h^(-1),respectively;C_(max) was 183,448,1 621 and 12.0 μg/L,respectively.C_(max) and AUC_((0-t)) increased linearly in dose dependent manner in the intravenous administration group.The exposure in the gavage was equivalent to that in the intravenous low-dose group,and the maximum plasma concentration was much lower than that in the intravenous low-dose group.The bioavailability of mosapride citrate suspension was 4.45%.Conclusion:Intravenous administration of mosapride citrate can achieve the effect of 10 to 100 times of dose by intragastric administration.Compared with oral administration,it has the characteristics of lower effective dose and faster effective,which has certain clinical development value.