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MDR1 P-glycoprotein (P-gp) plays an important role in determining drug disposition. The purpose of the present study was to establish in vitro models to predict the in vivo function of P-gp. As an in vitro method, the transcellular transport of 12 compounds across the monolayer of Caco-2- and MDR1-transfected cells was examined. The ability of these compounds to stimulate the ATP hydrolysis was also determined using the isolated membrane fraction expressing P-gp. As a parameter to describe the in vivo P-gp function, we calculated the brain-to-plasma concentration ratio of compounds in mdr1a/1b knockout mice divided by the same ratio in wild type mice. A good correlation was observed between the in vitro flux ratio across the monolayer and in vivo P-gp function for 12 compounds. Although all compounds that stimulated ATP hydrolysis were significantly transported by P-gp, some compounds were transported by P-gp without significantly affecting ATP hydrolysis. Collectively, the in vitro flux ratio across monolayers of P-gp-expressing cells may be used to predict in vivo P-gp function. The extent of ATP-hydrolysis in vitro may also be a useful parameter for in vivo prediction, particularly for eliminating P-gp substrates in high-throughput screening procedures.


Y Adachi, H Suzuki, Y Sugiyama. Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharmaceutical research. 2001 Dec;18(12):1660-8

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PMID: 11785684

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