盐酸特拉唑嗪胶囊在Beagle犬体内药动学与体外溶出的相关性研究

Correlation between pharmacokinetics and in vitro dissolution of terazosin hydrochloride capsules in Beagle dogs

目的:评价盐酸特拉唑嗪胶囊体外溶出度,建立液质联用(LC-MS/MS)法测定Beagle犬血浆中特拉唑嗪的浓度,并研究盐酸特拉唑嗪胶囊在健康Beagle犬体内的药动学;结合体外溶出情况,进行相关性分析,为后续的人体生物等效性试验提供指导。方法:采用桨法(加沉降篮)在4种不同介质(900 mL,50r·min^-1)中进行溶出度试验,并用HPLC法测定特拉唑嗪溶出度;10只Beagle犬分别单剂量交叉灌服盐酸特拉唑嗪胶囊受试制剂或参比制剂2 mg;采用LC-MS/MS法测定血浆中特拉唑嗪的浓度,使用DAS 3. 2. 8软件进行药动学参数计算。结果:除pH 4. 0介质外,其他介质中2种制剂体外溶出度良好。所建立的LCMS/MS法能满足生物样品分析要求。受试制剂和参比制剂主要药动学参数如下:t1/2分别为(8. 697±1. 377)和(9. 202±2. 925) h,Cmax分别为(19. 19±5. 623)和(17. 900±3. 826) ng·mL^-1,Tmax分别为(2. 6±1. 519)和(2. 575±1. 519) h,AUC0-t分别为(230. 81±37. 361)和(215. 505±21. 725) ng·h·mL^-1,AUC0-∞分别为(238. 094±36. 879)和(224. 920±23. 025) ng·h·mL^-1;以参比制剂为对照,估算受试制剂的AUC0-t相对生物利用度为(106. 9±11. 5)%,AUC0-∞相对生物利用度为(105. 9±12. 5)%,两者在Beagle犬体内生物等效。结论:本文建立的LC-MS/MS法简便快速,灵敏准确,适用于研究特拉唑嗪胶囊在Beagle犬体内的药动学行为。盐酸特拉唑嗪胶囊在p H 4. 0介质的溶出曲线与参比制剂存在较大差异,但对盐酸特拉唑嗪胶囊在健康Beagle犬体内的药动学没有显著影响;其他介质溶出曲线相似。综合分析该制剂为速释制剂、空腹状态给药等因素,推测p H 1. 0介质对其在Beagle犬体内的药动学影响较大且有一定相关性,但与人体药动学的关系尚需进一步验证。

Objective:To evaluate the dissolution rate of terazosin hydrochloride capsules in vitro;to establish an LC-MS/MS method to determine the plasma concentration of terazosin in Beagle dogs;and to study the Pharmacokinetics of terazosin hydrochloride capsules in healthy Beagle dogs;to provide guidance for subsequent human bioequivalence tests by combining in vitro dissolution and performing correlation analysis.Methods:The paddle method(plus settling basket)was used for dissolution test in 4 different dissolution media(900 mL,50r·min^-1),and the dissolution rate of terazosin was determined by HPLC method.Ten Beagle dogs were given a single dose of 2 mg terazosin hydrochloride capsules as a test or reference formulation.The concentration of terazosin in plasma was determined by LC-MS/MS method,and the pharmacokinetic parameters were calculated using DAS3.2.8 software.Results:Except for the p H 4.0 media,the dissolution of the two preparations in other media was good.The established LC-MS/MS method met the requirements of biological sample analysis.The main pharmacokinetic parameters of the test and reference preparations are as follows:t1(8.697±1.377)and(238.094±36.879)and(224.920±23.025)ng·h·mL^-1.Taking the reference preparation as a control,the relative bioavailability of the AUC0-tof the test preparation is estimated to be(106.9±11.5)%,and the relative bioavailability of AUC0-(105.9±12.5)%,both of which were bioequivalent in Beagle dogs.Conclusion:The LC-MS/MS method established in this paper is simple,rapid,sensitive and accurate,and is suitable for the pharmacokinetic behavior study of terazosin in Beagle dogs.The dissolution profile of terazosin hydrochloride capsules in the pH 4.0 media is significantly different from the reference preparation,but it has no significant effect on the pharmacokinetics of terazosin hydrochloride capsules in healthy Beagle dogs.The dissolution profiles of other media are similar.Comprehensive analyzing the factors such as immediate-release preparation and fasting administration,it is speculated that pH 1.0 media has a large effect on the pharmacokinetics of Beagle dogs and has a certain correlation,but the relationship with human pharmacokinetics needs to be further verified in human BE tests.