ABSENCE OF THE MDR1A P-GLYCOPROTEIN IN MICE AFFECTS TISSUE DISTRIBUTION AND PHARMACOKINETICS OF DEXAMETHASONE, DIGOXIN, AND CYCLOSPORINE-A

We have previously shown that absence of the mouse mdr1a (also called mdr3) P-glycoprotein in mdr1a (-/-) ''knock-out'' mice has a profound effect on the tissue distribution and elimination of vinblastine and i vermectin, and hence on the toxicity of these compounds. We show here that the mouse mdr1a and the human MDR1 P-glycoprotein actively transp ort ivermectin, dexamethasone, digoxin, and cyclosporin A and, to a le sser extent, morphine across a polarized kidney epithelial cell layer in vitro, Injection of these radio-labeled drugs in mdr1a (-/-) and mi ld-type mice resulted in markedly (20- to 50-fold) higher levels of ra dioactivity in mdr1a (-/-) brain for digoxin and cyclosporin A, with m ore moderate effects for dexamethasone (2- to 3-fold) and morphine (1. 7-fold), Digoxin and cyclosporin A were also more slowly eliminated fr om mdr1a (-/-) mice. Our findings show that P-glycoprotein can be a ma jor determinant for the pharmacology of several medically important dr ugs other than anti-cancer agents, especially in the blood-brain barri er, These results may explain a range of pharmacological interactions observed between various drugs in patients.