泰地罗新在比格犬体内的药动学研究

Study on Pharmacokinetics of Tildipirosin in Beagle Dogs

为了获得泰地罗新在比格犬体内的药动学数据,选取15只比格犬分为3组,泰地罗新以推荐剂量4 mg/kg分别对比格犬进行肌肉和皮下注射,以2 mg/kg剂量进行静脉注射;于不同时间点采集比格犬血液,离心获得血浆,经处理后应用高效液相色谱测定血液中的药物含量;应用Winnonlin软件中的非房室模型对血药浓度-时间数据进行分析,获得泰地罗新在比格犬体内的药动学数据。结果显示,泰地罗新标准曲线性关系良好,相关系数超过0.99;检测限为5 ng/mL,定量限为10 ng/mL;5、50、500 ng/mL浓度的加样回收率在80%~120%之间,日内和日间变异系数均小于10%;稳定性试验中待测药物的响应值均低于20%。泰地罗新静脉、肌肉、皮下注射后在比格犬体内的T_(1/2e)分别为48.23 h±12.57 h、71.71 h±38.17 h、75.29 h±32.32 h;T_(max)分别为0.11 h±0.04 h、0.07 h±0.03 h、0.10 h±0.04 h;C_(max)分别为446.91 ng/mL±57.68 ng/mL、732.09 ng/mL±87.94 ng/mL、635.52 ng/mL±94.39 ng/mL;AUC_(0-t)分别为12661.11 ng·h/mL±3047.21 ng·h/mL、22898.57 ng·h/mL±5079.82 ng·h/mL、20974.46 ng·h/mL±4789.36 ng·h/mL;MRT_(last)分别为49.33 h±5.67 h、63.05 h±5.32 h、67.37 h±7.21 h;肌肉注射的生物利用度为90.42%±4.84%,皮下注射的生物利用度为82.83%±7.96%。泰地罗新在比格犬血液中吸收快、消除缓慢,血药浓度较高,皮下注射和肌肉注射的生物利用度高。

In order to obtain the pharmacokinetic data of tildipirosin in beagles,15 beagle dogs were selected as 3 groups.Tildipirosin was administered intramuscularly and subcutaneously to beagle dogs at the recommended dose of 4 mg/kg,and intravenously at a dose of 2 mg/kg.The blood samples were collected at different time points,and centrifuged to obtain plasma samples.After pretreatment procedure,the drug concentration in plasma was determined by HPLC.The non-compartmental analysis in Winnonlin software was used to analyze plasma concentration-time data and obtain pharmacokinetic data of tildipirosin in beagle dogs.The results showed that the standard curve of tildipirosin was good,with a correlation coefficient over 0.99.The detection limit was 5 ng/mL,and the quantification limit was 10 ng/mL.The recovery rates of samples at concentrations of 5,50 and 500 ng/mL ranged from 80%to 120%,and the intra-day and inter-day coefficient of variation were both less than 10%.The response values of the tested drugs in the stability test were all below 20%.The results of pharmacokinetic experiments showed that the T_(1/2e)in beagle dogs after intravenous,intramuscular,and subcutaneous injection of tildipirosin were 48.23 h±12.57 h,71.71 h±38.17 h,and 75.29 h±32.32 h,respectively.The values of T_(max)were 0.11 h±0.04 h,0.07 h±0.03 h,0.10 h±0.04 h,respectively.The values of C_(max)were 446.91 ng/mL±57.68 ng/mL,732.09 ng/mL±87.94 ng/mL,635.52 ng/mL±94.39 ng/mL,respectively.The values of AUC_(0-t)were 12661.11 ng·h/mL±3047.21 ng·h/mL,22898.57 ng·h/mL±5079.82 ng·h/mL,20974.46 ng·h/mL±4789.36 ng·h/mL,respectively.The values of MRT_(last)were 49.33 h±5.67h,63.05 h±5.32 h,67.37 h±7.21 h,respectively.The bioavailability of intramuscular injection was 90.42%±4.84%,and that of subcutaneous injection was 82.83%±7.96%.The absorption of tildipirosin in the blood of beagle dogs was fast,the elimination was slow,the blood concentration was high,and the bioavailability of subcutaneous injection and intramuscular injection was high.