醋酸艾塞那肽在Wistar大鼠体内的药物代谢动力学研究

研究醋酸艾塞那肽（exendin-4）在Wistar大鼠体内的药物代谢动力学，组织分布以及排泄特征。IODOGEN（四氯二苯基苷脲）法制备^125I-exendin-4，大鼠皮下或静脉注射，^125I-exendin-4，以放射性核素示踪动力法检测血液中的药物浓度，由非房室模型评价药物动力学参数。同时研究了大鼠皮下注射^125I-exendin-4后的组织分布和排泄。大鼠皮下注射^125I-exendin-4后Tmax和t1/2分别是（0．25±0．02）h和（1．28±0．14）h，绝对生物利用度为（65．5±10．2）％；^125I-exendin-4的分布快速而广泛，其中以肾脏中最高，而在脑组织中只有微量^125I-exendin-4；^125I-exendin-4主要随尿液排泄。实验结果与国外公布的实验数据基本一致。醋酸艾塞那肽在大鼠中的药物代谢动力学参数为临床试验提供了科学依据。

Pharmacokinetics of exendin-4 in Wistar rots

To characterize the preclinical pharmacokinetics, tissue distribution and excretion profiles of exendin-4 in healthy Wistar rats were studied. Exendin-4 was radioiodinated by the IODOGEN （1,3,4,6-tetrachloro-3 alpha, 6 alphadiphenylglucoluril） method. Pharrnacokinetic properties of ^125I-exendin-4 were examined after a single s.c. and i.v. injection, respectively. Tissue distri- bution and urinary, fecal, and biliary excretion patterns of ^125I-exendin-4 were also investigated following a single s.c. injection. Exendin-4 was rapidly distributed and cleared with t1/2 of （0.48 ± 0.03） h after a single i.v. injection. Following a single s.c. administration, exendin-4 exhibited rapid and considerable absorption with Tmax of （0.25± 0.02） h and declined with the elimination t1/2 of（1.28± 0.14） h. The absolute bioavailability was （65.5 ± 10.2） %. The radioactivity was widely distributed and rapidly diminished in most tissues. The kidney contained the highest radioactivity and the distribution of ^125I-exendin-4 to the brain was minimal. The major elimination route was urinary excretion. The pharmacokinetic properties of exendin-4 obtained from the present study closely matched those reported in previous studies in rats. Pharmacokinetics profiles of exendin-4 in rats are warranted for the design of future clinical trials.