Quantitative evaluation of the function of small intestinal P-glycoprotein:: Comparative studies between in situ and in vitro
Quantitative evaluation of the function of small intestinal P-glycoprotein:: Comparative studies between in situ and in vitro
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DOI：
10.1023/a:1025088628787
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发表时间：
2003-08-01
影响因子：
3.7
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Adachi, Y;Suzuki, H;Sugiyama, Y
目的. MDR 1 P-糖蛋白（P-gp）底物药物的肠道吸收程度可能受到P-gp表达水平的个体间差异和/或同时给予P-gp底物/抑制剂的影响。本研究的目的是检查在何种程度上的肠吸收的影响P-gp是否可以预测从体外实验。采用mdr 1a/1b（-/-）小鼠和正常小鼠进行12种化合物的在体肠灌流实验，测定渗透性-表面积（PS）乘积。将测定的肠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表达和亲本LLC-PK 1单层的跨细胞转运来测定。在体实验结果表明，P-gp对小肠吸收的影响程度依次为奎尼丁>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。肠灌流中的P-gp功能与LLC-PK 1单层中的P-gp功能之间存在显著相关性。体外跨P-gp表达单层细胞的跨细胞转运可用于预测P-gp对肠吸收的影响程度。
Purpose. 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.Methods. The in situ intestinal perfusion experiments were performed for 12 compounds in mdr1a/1b (-/-) 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.Results. 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-PK1 monolayers.Conclusion. 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.