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Research Article Free access | 10.1172/JCI118699

P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.

A H Schinkel, E Wagenaar, C A Mol, and L van Deemter

The Netherlands Cancer Institute, Division of Molecular Biology, 1066 CX Amsterdam, The Netherlands.

Find articles by Schinkel, A. in: PubMed | Google Scholar

The Netherlands Cancer Institute, Division of Molecular Biology, 1066 CX Amsterdam, The Netherlands.

Find articles by Wagenaar, E. in: PubMed | Google Scholar

The Netherlands Cancer Institute, Division of Molecular Biology, 1066 CX Amsterdam, The Netherlands.

Find articles by Mol, C. in: PubMed | Google Scholar

The Netherlands Cancer Institute, Division of Molecular Biology, 1066 CX Amsterdam, The Netherlands.

Find articles by van Deemter, L. in: PubMed | Google Scholar

Published June 1, 1996 - More info

Published in Volume 97, Issue 11 on June 1, 1996
J Clin Invest. 1996;97(11):2517–2524. https://doi.org/10.1172/JCI118699.
© 1996 The American Society for Clinical Investigation
Published June 1, 1996 - Version history
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Abstract

The mouse mdr1a (also called mdr3) P-GP is abundant in the blood-brain barrier, and its absence in mdr1a (-/-) 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 (-/-) 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 (-/-) mice. mdr1a (-/-) 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.

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