Absence of the mdrla P-Glycoprotein in Mice Affects Tissue Distribution and Pharmacokinetics of Dexamethasone

We have previously shown that absence of the mouse mdrla (also called mdr3) P-glycoprotein in mdrla (-/-) "knock-out " mice has a profound effect on the tissue distribution and elimination of vinblastine and ivermectin, and hence on the toxicity of these compounds. We show here that the mouse mdrla and the human MDR1 P-glycoprotein actively transport ivermectin, dexamethasone, digoxin, and cyclo-sporin A and, to a lesser extent, morphine across a polarized kidney epithelial cell layer in vitro. Injection of these radio-labeled drugs in mdrla (-/-) and wild-type mice resulted in markedly (20- to 50-fold) higher levels of radioactivity in mdrla (-/-) brain for digoxin and cyclosporin A, with more moderate effects for dexamethasone (2- to 3-fold) and morphine (1.7-fold). Digoxin and cyclosporin A were also more slowly eliminated from mdrla (-/-) mice. Our find-ings show that P-glycoprotein can be a major determinant for the pharmacology of several medically important drugs other than anti-cancer agents, especially in the blood-brain barrier. These results may explain a range of pharmacologi-cal interactions observed between various drugs in patients