Adachi Yasuhisa, Suzuki Hiroshi, Sugiyama Yuichi
School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Pharm Res. 2003 Aug;20(8):1163-9. doi: 10.1023/a:1025088628787.
The extent of intestinal absorption of MDR1 P-glycoprotein (P-gp) substrate drugs may be affected by interindividual differences in the expression level of P-gp, and/or by simultaneously administered P-gp substrates/inhibitors. The purpose of the present study is to examine whether the extent to which the intestinal absorption is affected by P-gp can be predicted from in vitro experiments.
The in situ intestinal perfusion experiments were performed for 12 compounds in mdrla/lb (-/-) and normal mice to determine the permeability-surface area (PS) product. Thus determined intestinal P-gp function was compared with the in vitro P-gp function, which was determined by comparing the transcellular transport across human P-gp expressing and parental LLC-PK1 monolayers.
In situ experimental results revealed that the extent to which the intestinal absorption is affected by P-gp was in the following order: quinidine > ritonavir > loperamide, verapamil, daunomycin > digoxin, cyclosporin A > dexamethasone, and vinblastine. A significant correlation was observed between P-gp function determined in the intestinal perfusion and that in LLC-PKI monolayers.
The in vitro transcellular transport across P-gp expressing monolayers may be used to predict the extent to which the intestinal absorption is affected by P-gp.
多药耐药蛋白1（MDR1）P-糖蛋白（P-gp）底物药物的肠道吸收程度可能受P-gp表达水平的个体差异和/或同时给予的P-gp底物/抑制剂的影响。本研究的目的是检验是否可以通过体外实验预测肠道吸收受P-gp影响的程度。
对12种化合物在mdrla/lb（-/-）小鼠和正常小鼠中进行原位肠道灌注实验，以确定通透率-表面积（PS）乘积。将由此确定的肠道P-gp功能与体外P-gp功能进行比较，体外P-gp功能通过比较跨人P-gp表达单层细胞和原始LLC-PK1单层细胞的跨细胞转运来确定。
原位实验结果表明，肠道吸收受P-gp影响的程度依次为：奎尼丁＞利托那韦＞洛哌丁胺、维拉帕米、柔红霉素＞地高辛、环孢素A＞地塞米松和长春碱。在肠道灌注实验中测定的P-gp功能与在LLC-PK1单层细胞中测定的P-gp功能之间观察到显著相关性。
体外跨P-gp表达单层细胞的跨细胞转运可用于预测肠道吸收受P-gp影响的程度。
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