他克莫司缓释胶囊在Beagle犬体内的药动学与生物等效性研究

Pharmacokinetics and Bioequivalence Research of Tacrolimus Sustained Release Capsule in Beagle Dogs

目的研究他克莫司片在beagle犬体内的药动学和生物等效性。方法采用随机自身交叉对照实验,将6例beagle犬按照先参比制剂后受试制剂、先受试制剂后参比制剂2种给药序列进行随机分配,每组3例,每个周期单次口服3 mg参比制剂或受试制剂,用LC-MS/MS测定样品浓度,再采用Win Nonlin 6.3版软件计算药动学参数,比较受试制剂和参比制剂的生物等效性。结果受试制剂和参比制剂他克莫司药动学参数Tmax分别为(1.08±0.41)h和(0.83±0.13)h,Cmax分别为(11.63±1.35)ng·mL^(-1)和(14.83±4.70)ng·mL^(-1),AUC0-48分别为(62.93±32.06)h·ng·mL^(-1)和(62.89±28.14)h·ng·mL^(-1),半衰期t1/2分别为(10.90±4.26)h和(10.99±3.12)h。Beagle犬口服受试制剂后Tmax,t1/2在受试制剂和参比制剂间无明显差异;峰浓度Cmax约为参比制剂给药后的85.34%,90%置信区间为87.21%~102.16%;相对生物利用度(AUClast,受试/AUClast,参比)为99.42%,90%置信区间为85.53%~115.56%,表明受试制剂和参比制剂较接近。结论他克莫司缓释胶囊受试制剂和参比制剂具有生物等效性。

OBJECTIVE To investigate pharmacokinetic and bioequivalence of tacrolimus sustained release capsule in beagle dogs. METHODS Six beagle dogs were randomly divided into 2 groups. A single oral dose of 3 mg of test or reference capsules were delivered to each dog in an open crossover test. The blood concentration of tacrolimus was determined by LC-MS/MS detection, and the pharmacokinetic parameters were calculated with Win Nonlin 6.3 program by a computer. Based on the parameters of pharmacokinetic and relative bioavailability, the bioequivalence of tacrolimus was evaluated. RESULTS The pharmacokinetic parametes of the test and reference preperations were as follows： Tmax was（1.08±0.41）h and（0.83±0.13）h, Cmax was（11.63±1.35）ng·mL^-1 and（14.83±4.70）ng·mL^-1, AUC0-48 was（62.93±32.06）h·ng·mL^-1 and（62.89±28.14）h·ng·mL^-1, t1/2 was（10.90±4.26）h and（10.99±3.12）h in 2 groups respectively. After taking oral test capsule, beagle dog shows no noticeable Tmax,t1/2 variation between test and reference capsule; The Cmax is about 85.34% of the reference capsule that is located within the 90% confidence interval of 87.21%-102.16%; The relative bioequivalence（AUClast,test /AUClast,reference） is 99.42%, that is with in the 90% confidence interval of 85.53%-115.56%, it shows that the test and reference capsule is close in effects. CONCLUSION The test and reference preparation of tacrolimus are bioequivalent.