Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction
Evaluation of increased bioavailability of tacrolimus in rats with experimental renal dysfunction
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DOI：
10.1211/0022357021771931
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发表时间：
2002-01-01
影响因子：
3.3
通讯作者：
Inui, KI
中科院分区：
文献类型：
--
作者：
Okabe, H;Yano, I;Inui, KI
本研究以顺铂诱导的肾衰竭模型大鼠为模型，观察了肾衰竭对他克莫司肝、肠溶出的影响，探讨了他克莫司生物利用度增加的机制。通过静脉内、门静脉内和肠内输注评价他克莫司在肝和肠中的提取。肠代谢和吸收速率分别通过与药物溶液孵育的离体肠和通过原位环方法估计。与正常大鼠相比，肾功能衰竭大鼠肠内输注他克莫司后的血药浓度显著升高。肾功能衰竭大鼠门静脉输注他克莫司的血药浓度与剂量呈非线性关系，并较正常大鼠升高。肠代谢没有改变，但肾功能不全大鼠的肠吸收率显著增加。这些结果表明，他克莫司在肾功能衰竭大鼠的肝脏代谢受损，肾功能不全时肠道吸收速率加快，随后肝脏提取物部分饱和，这可能是他克莫司生物利用度增加的机制之一。
The effects of renal failure on the hepatic and intestinal extraction of tacrolimus were evaluated to examine the mechanisms for the increased bioavailability of this drug in cisplatin-induced renal failure model rats. Tacrolimus extractions in the liver and intestine were evaluated by intravenous, intraportal and intraintestinal infusion. The intestinal metabolism and absorption rate were estimated by incubating the isolated intestine with drug solution and by an in situ loop method, respectively. Blood concentrations of tacrolimus following the intraintestinal infusion were significantly increased in rats with renal failure compared with those in normal rats. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine from rats with renal dysfunction. These results suggest that the hepatic metabolism of tacrolimus is impaired in rats with renal failure, and that the accelerated absorption rate in the intestine in renal dysfunction is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.