6种常用抗寄生虫药在鸡的生物药剂学分类研究

Biopharmaceutical classification system research for six commonly used anti-parasitic drugs in chickens

[目的]本研究拟建立基于靶动物生理参数的禽用药物溶解度和渗透性测定方法,并依据生物药剂学分类系统(Biopharmaceutics Classification System,BCS)对6种兽医临床常用抗寄生虫药(吡喹酮、阿苯达唑、盐酸左旋咪唑、盐酸氨丙啉、地克珠利、常山酮)进行分类。[方法]1日龄AA内鸡90只饲养至8周龄,分别于1、4和8周龄时测定鸡体温、胃肠液体积和胃肠pH值,通过计算剂量数(Do)确定6种药物的生理溶解度及分类;以酒石酸美托洛尔为高低渗透性参考标准,结合单层细胞模型和鸡小肠原位灌流试验测定的药物表观渗透系数(Papp)和有效渗透系数(Peff),确定药物的渗透性并进行分类。[结果]将鸡常用药物溶解度的测定条件规定为41℃及pH1~8的水性缓冲溶液,高溶解度的定义为药物单次给药的最高剂量能完全溶解于21 mL(进食)或7 mL(禁食)的水性缓冲溶液中。Do计算结果表明盐酸左旋咪唑、盐酸氨丙啉和常山酮在鸡进食及禁食条件下均为高溶解度药物,吡喹酮、阿苯达唑和地克珠利则为低溶解度药物。单层细胞模型法测得吡喹酮、阿苯达唑和盐酸左旋咪唑的Papp分别为12.92×10^-6、15.12×10^-6和14.64×10^-6 cm·s^-1,均高于酒石酸美托洛尔(6.58×10^-6 cm·s^-1),故为高渗透性药物。鸡小肠原位灌流试验结果表明,6种药物在鸡体内的Peff分别为0.76×10^-4、1.35×10^-4、0.93×10^-4、0.05×10^-4、0.66×10^-4和0.31×10^-4 cm·s^-1,其中吡喹酮、阿苯达唑和盐酸左旋咪唑的Peff均高于酒石酸美托洛尔(0.68×10^-4 cm·s^-1),为高渗透性药物,与单层细胞模型法测定的结果相一致。综合6种药物的溶解度和渗透性测定结果,确定6种药物的BCS分类为:盐酸左旋咪唑为Ⅰ类药物;吡喹酮和阿苯达唑为Ⅱ类药物;盐酸氨丙啉和常山酮为Ⅲ类药物;地克珠利为Ⅳ类药物。[结论]初步确定了鸡常用药物生理溶解度测定条件以及渗透性测定方法,完成了6种常用抗寄生虫药在鸡的BCS分类,为鸡常用药物BCS框架的建立奠定了基础。

[Objectives]This study intends to establish a biopharmaceutical classification system(BCS)method for determining the solubility and permeability of veterinary drugs based on the physiological parameters of target animals,and then to classify six antiparasitic drugs(praziquantel,albendazole,levamisole hydrochloride,amprolium hydrochloride,diclazuril and halofuginone)which are often used in the veterinary clinic.[Methods]The body temperature,the volume and pH of gastrointestinal of chickens were determined experimentally at the age of 1,4 and 8-week old,then the physiological solubility was determined and classified by calculating the dose number(Do)of each drug.The apparent permeability coefficient(Papp)and effective permeability coefficient(Peff)were determined using monolayer cell model and chicken small intestine in situ perfusion,respectively,and based on these parameters,the drug permeability was classified by comparing with the high-permeability drug metoprolol.[Results]The equilibrium solubility of each drug was measured in 41℃buffer solutions under pH values of 1,3,5,7 and 8,respectively,and a drug is considered as highly soluble in chicken BCS when the highest dose strength is soluble in 21 mL(fed)or 7 mL(fasted)over the pH range of 1-8 at 41℃.The result showed that levamisole hydrochloride,amprolium hydrochloride and halofuginone were high solubility drugs under both feeding and fasting conditions.Praziquantel,albendazole and diclazuril were low solubility drugs.The Papp of praziquantel,albendazole and levamisole hydrochloride was 12.92×10^-6,15.12×10^-6 and 14.64×10^-6 cm·s^-1,respectively,which were higher than that of metoprolol(6.58×10^-6 cm·s^-1),identified as highly permeable drugs.The results of in situ perfusion of small intestine showed that the Peff of these six drugs were 0.76×10^-4,1.35×10^-4,0.93×10^-4,0.05×10^-4,0.66×10^-4 and 0.31×10^-4 cm·s^-1,respectively,among which the Peff of praziquantel,albendazole and levamisole hydrochloride were higher than that of metoprolol(0.68×10^-4 cm·s^-1),thus were considered as highly permeable drugs.The result was consistent with the results of monolayer cell model.Based on the solubility and permeability results of each drug,levamisole hydrochloride was classified as classⅠdrug;praziquantel and albendazole were classⅡdrugs;ampicillin hydrochloride and abenzophenone were classⅢdrugs;diclazuril was a classⅣdrug.[Conclusions]This work highlights some of the significant challenges that would be encountered in developing a chicken BCS,and this valuable information could be served as a helpful tool during chicken products development and to minimize the potential risks when developing formulations.