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Interplay between in tasting and liver for the first-pass metabolism of orally administered drugs

口服药物首过代谢中味觉和肝脏之间的相互作用

基本信息

批准号：
13672384
负责人：
HASHIMOTO Yukiya
金额：
$ 0.58万
依托单位：
TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Tacrolimus has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. The rate of absorption of tacrolimus in the intestine was rapid, and the drug was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 26% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver, and that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration. Furthermore, the effects of renal failure on the pharmacokinetics and bioavailability of tacrolimus were investigated in cisplatin-induced renal failure model rats. The bioavailability of tacrolimus was increased by 35% in rats with impaired renal function as compared with normal control. 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 in rats with renal failure. These results suggested that the hepatic metabolism of tacrolimus is impared in rats with renal failure, and that the accelerated absorption rate in the intestine in renal failure is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.

在临床使用中，他克莫司口服给药后生物利用度差且变化多端。我们研究了大鼠肠道代谢对他克莫司首过效应的影响。他克莫司在肠道内的吸收速度很快，肠道给药后药物几乎完全吸收。门脉内和肠内给药后他克莫司的生物利用度分别约为40%和26%，表明他克莫司在肠道和肝脏中代谢，并且他克莫司在肠道中的代谢有助于其口服给药后广泛且可变的首过代谢。此外，在顺铂诱导的肾衰竭模型大鼠中研究了肾衰竭对他克莫司药代动力学和生物利用度的影响。与正常对照组相比，肾功能受损大鼠中他克莫司的生物利用度增加了 35%。肾功能衰竭大鼠门静脉输注时他克莫司血药浓度与剂量呈非线性关系，且较正常大鼠血药浓度升高。肾衰竭大鼠肠道代谢没有改变，但肠道吸收率显着增加。这些结果表明，肾衰竭大鼠中他克莫司的肝脏代谢受到损害，肾衰竭时肠道吸收速率加快，随后肝提取部分饱和，这可能是他克莫司生物利用度增加的机制之一。