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The mouse mdr1a (also called mdr3) P-GP is abundant in the blood-brain barrier, and its absence in mdr1a ( Ϫ / Ϫ ) mice leads to highly increased levels of the drugs ivermectin, vinblastine, digoxin, and cyclosporin A in the brain. We show here that the drugs loperamide, domperidone, and ondansetron are transported substrates for the mouse mdr1a P-GP and its human homologue MDR1. Phenytoin is a relatively weaker substrate for each, and the drugs haloperidol, clozapine, and flunitrazepam are transported hardly or not at all. Tissue distribution studies demonstrated that the relative brain penetration of radiolabeled ondansetron and loperamide (and their metabolites) is increased four-and sevenfold, respectively, in mdr1a ( Ϫ / Ϫ ) mice. A pilot toxicity study with oral loperamide showed that this peripherally acting antidiarrheal agent gains potent opiatelike activity in the central nervous system of mdr1a ( Ϫ / Ϫ ) mice. mdr1a ( Ϫ / Ϫ ) mice also showed increased sensitivity to neurolepticlike side effects of oral domperidone. These results point to the possible role that the drug-transporting P-GP(s) may play in the clinical use of many drugs, especially those with potential targets in the central nervous system. ( J. Clin. Invest. 1996. 97:2517-2524.)

We have previously shown that absence of the mouse mdrla (also called mdr3) P-glycoprotein in mdrla ( -/-) "knockout" 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 cyclosporin A and, to a lesser extent, morphine across a polarized kidney epithelial cell layer in vitro. Injection of these radiolabeled 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 findings 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 pharmacological interactions observed between various drugs in patients. (J. Clin. Invest. 1995.96:1698-1705