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

细胞色素P450 (CYP) 3A在肠道和肝脏均有表达，在临床研究中，肠道代谢对他克莫司和其他CYP3A底物的口服生物利用度有很大影响。我们研究了大鼠肠道代谢对他克林首过效应的贡献。他克莫司给予大鼠静脉、口内或肠内注射。在240分钟的时间内采集血液样本，并测量血液中他克莫司的浓度。研究了他克莫司在肠道和肝脏中的提取比例。他克莫司在肠内吸收速度快，经肠给药后几乎完全吸收。门内给药和肠内给药后，他克莫司的生物利用度分别约为40%和25%，表明他克莫司在肠道和肝脏均有代谢。他克莫司在大鼠肠外翻囊中代谢显著。目前的研究表明，他克莫司在肠道内的代谢有助于其广泛和可变的口服给药后的第一次代谢。此外，p -糖蛋白的排出以及肠道内CYP3A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.