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

关键词:  他克莫司  Beagle犬  药动学  生物等效性

Key words:  tacrolimus  beagle dogs  pharmacokinetics  bioequivalence

摘要:

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WinNonlin 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T_max分别为(1.08±0.41)h和(0.83±0.13)h，C_max分别为(11.63±1.35)ng·mL^-1和(14.83±4.70)ng·mL^-1，AUC_0-48分别为(62.93±32.06)h·ng·mL^-1和(62.89±28.14)h·ng·mL^-1，半衰期t_1/2分别为(10.90±4.26)h和(10.99±3.12)h。Beagle犬口服受试制剂后T_max，t_1/2在受试制剂和参比制剂间无明显差异；峰浓度C_max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(AUC_{last，受试}/AUC_{last，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。

Abstract:

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 WinNonlin 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: T_max was (1.08±0.41)h and (0.83±0.13)h, C_max was (11.63±1.35)ng·mL^-1 and (14.83±4.70)ng·mL^-1, AUC_0-48 was (62.93±32.06)h·ng·mL^-1 and (62.89±28.14)h·ng·mL^-1, t_1/2 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 T_max，t_1/2 variation between test and reference capsule; The C_max is about 85.34% of the reference capsule that is located within the 90% confidence interval of 87.21%-102.16%; The relative bioequivalence (AUC_last，test/AUC_{last，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.