Analysis of barrier function of intestinal drug-metabolizing enzymes and transporters

研究表明，细胞色素P450（CYP）3A在肠道和肝脏中表达，在临床研究中，肠道代谢对他克莫司和其他CYP 3A底物的口服生物利用度有很大贡献。我们研究了大鼠肠道代谢对他克莫司首过效应的影响。在240分钟内收集血液样本，并测量血液他克莫司浓度。考察了他克莫司在小肠和肝脏中的提取率。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25%，表明他克莫司在肠和肝中代谢。他克莫司在外翻肠囊内有明显的代谢，提示他克莫司在肠内的代谢是其口服给药后广泛而多变的首过代谢的一部分。此外，通过P-糖蛋白的排斥作用以及在肠道中通过CYP 3A的代谢，可能有助于某些药物的首过效应，这些药物是这些蛋白质的底物。

It has been suggested that cytochrome P450 (CYP) 3A is expressed in the intestine as well as liver, and that the intestinal metabolism contributes largely to the oral bioavailability of tacrolimus and other CYP3A substrates in clinical studies. We investigated the contribution of intestinal metabolism to the first-pass effect of tacrolims in rats.Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. 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 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. Tacrolimus was significantly metabolized in the everted sac of the rat intestine.The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first-pass metabolism following the oral administration. In addition, the exorption by P-glycoprotein, as well as metabolism by CYP3A in the intestine, may contribute to the first pass effects of some drugs, which are substrates of these proteins.