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

他克莫司在临床应用中口服给药后生物利用度较差且变化不定。我们研究了肠道代谢对大鼠他克莫司首过效应的贡献。他克莫司在肠道的吸收速度快，给药后药物几乎完全吸收。门静脉和肠内给药后，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和可变的首过代谢。此外，在顺铂诱导的肾功能衰竭模型大鼠中，研究肾功能衰竭对他克莫司药代动力学和生物利用度的影响。他克莫司在肾功能损害大鼠体内的生物利用度比正常对照组增加35%。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，但在肾功能衰竭大鼠的肠道吸收率显着增加。结果提示，他克莫司在肾功能衰竭大鼠体内的肝脏代谢不明显，肾功能衰竭大鼠肠道吸收加快后，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。

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.