纳川珠利在鸡体内的药动学特征及其与血浆蛋白结合率的研究

Studies on pharmacokinetics and plasma protein binding rate of nitromezuril in chickens

为了解纳川珠利在靶动物鸡体内的药动学参数,选用5周龄健康浦东黄羽肉鸡,按照体重单次灌服1、5和10mg/kg受试化合物,采用UPLC-UV方法检测待测样品中目标化合物的浓度,采用体外平衡渗析法检测血浆蛋白结合率。结果显示,纳川珠利在鸡体内的动力学过程符合一级消除动力学,吸收速率常数(Ka)平均0.74h-1,消除速率常数(Ke)平均0.076 3h-1,半衰期(t1/2)平均9.43h,表观分布容积(V/F)平均0.207 7L/kg,低、中、高给药剂量下血药质量浓度-时间曲线下面积AUC0→t分别为48.301 3、236.314 2和472.464 4μg/(mL·h),达峰时间(tmax)分别为4.003 4、2.501 4和3.500 0,达峰浓度(Cmax)分别为4.134 2、18.624 7和33.879 1μg/mL。鸡血浆蛋白的体外结合率大于96.3%,具有非浓度依赖的特点。上述结果表明,纳川珠利属于高血浆蛋白结合率化合物,在鸡体内属一级动力学消除,半衰期较长,代谢较慢,在与其他药物共用时有产生竞争性结合的风险。

To investigate pharmacokinetic parameters of nitromezuril（NZL）,5-week-old healthy Pudong Yellow broilers were adopted and administrated at a single dose of 1,5and 10mg/kg NZL by gavage according to body weight.The equilibrium dialysis method was adopted to determine the in vitro plasma protein binding rate.The UPLC-UV method was applied to determine the concentration of NZL.In result,the dynamic process of NZL in chickens was followed first-order elimination kinetics and the absorption rate constant Ka,elimination rate constant Ke,half-life t1/2and the apparent volume of distribution V/F were 0.74h-1,0.076 3h-1,9.43 hand 0.207 7L/kg,respectively.At dosages of NZL 1,5and 10mg/kg according to body weight,the area under the curve for concentration versus time AUC0→twere 48.301 3,236.314 2,and 472.464 4μg/（mL·h）,peak time in concentration-time profile tmaxwere 4.003 4,2.501 4and 3.500 0,and peak concentration in concentration-time profile Cmaxwere 4.134 2,18.624 7and 33.879 1μg/mL,respectively.The in vitro chicken plasma protein binding rate was above 96.3%,which has the non concentration-dependent characteristic.These results demonstrated that NZL belongs to the high plasma protein binding rate compound and was eliminated in chickens according to first-order kinetics.NZL has the long half-life and the low apparent volume of distribution.It can be speculated with slow metabolic characteristics and the risks of competitive binding when used with other drugs.