权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

肠道药物代谢酶和转运蛋白的屏障功能分析

基本信息

批准号：
11672256
负责人：
YUKIYA Hashimoto
金额：
$ 2.3万
依托单位：
TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY (2000)Kyoto University (1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672256/
关键词：
bioavailability CYP3A4 transporter P-glycoprotein metabolism intestine tacrolimus

项目摘要

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.

临床研究表明，细胞色素 P450 (CYP) 3A 在肠道和肝脏中表达，肠道代谢很大程度上影响了他克莫司和其他 CYP3A 底物的口服生物利用度。我们研究了肠道代谢对大鼠他克莫司首过效应的影响。他克莫司通过静脉、门脉内或肠内给药给大鼠。在 240 分钟内收集血样，并测量血液中他克莫司浓度。研究了他克莫司在肠和肝脏中的提取率。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25%，表明他克莫司在肠道和肝脏中代谢。他克莫司在大鼠肠外翻囊中显着代谢。本研究表明，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，P-糖蛋白的提取以及肠道中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质的底物。