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Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2

Sasaki, Makoto and Suzuki, Hiroshi and Aoki, Jun and Ito, Kousei and Meier, Peter J. and Sugiyama, Yuichi. (2004) Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Molecular pharmacology, Vol. 66, H. 3. S. 450-459.

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Official URL: http://edoc.unibas.ch/dok/A5261596

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Abstract

We have proposed previously that the evaluation of transcellular transport across the double-transfected Madin-Darby canine kidney II (MDCK II) monolayer that expresses both human organic anion transporting polypeptide 4 (OATP2/SLC21A6) and multidrug resistance associated protein 2 (MRP2/ABCC2) on the basal and apical membranes, respectively, may be useful in characterizing human biliary excretion (J Biol Chem 277: 6497-6503, 2002). However, to demonstrate that this in vitro system represents in vivo biliary excretion, it is essential to compare in vitro data with in vivo biliary excretion. The problem is that we cannot determine the human biliary excretion for many ligands. In the present study, we have established a double-transfected MDCK II monolayer that expresses both rat Oatp4/Slc21a10 and Mrp2/Abcc2 on the basal and apical membranes, respectively, for the purpose of quantitatively comparing the clearance for transcellular transport with that for in vivo biliary excretion. The basal-to-apical transport of 17beta-estradiol-17beta-d-glucuronide, pravastatin, leukotriene C(4), cyclo-[D-Asp-Pro-d-Val-Leu-d-Trp] (BQ123), temocaprilat, and taurolithocholate 3-sulfate was significantly higher than that in the opposite direction in the double transfectant. Kinetic analysis suggested that that the rate-determining step of these compounds is the uptake process. The extent of the transcellular transport across the rat double-transfectant correlated well with that across the double-transfectant for human OATP2/SLC21A6 and MRP2/ABCC2. Moreover, considering the scaling factor, the clearance values for in vitro transcellular transport correlated well with those for in vivo biliary clearance. The double-transfected MDCK II monolayer may be useful in analyzing the hepatic vectorial transport of organic anions and in predicting in vivo biliary clearance.
Faculties and Departments:11 Rektorat und Verwaltung > Vizerektorat Forschung
UniBasel Contributors:Meier-Abt, Peter J.
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Academic Press
ISSN:0026-895X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:24
Deposited On:22 Mar 2012 13:41

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