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PMID: 7560060 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.

The Journal of clinical investigation ·Vol. 96 ·No. 4 ·1995-10-00 ·Pages 1698-705

Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P

Abstract

We have previously shown that absence of the mouse mdr1a (also called mdr3) P-glycoprotein in mdr1a (-/-) "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 mdr1a 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 radio-labeled drugs in mdr1a (-/-) and wild-type mice resulted in markedly (20- to 50-fold) higher levels of radioactivity in mdr1a (-/-) 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 mdr1a (-/-) 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.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis,physiology Animals Biological Transport Cardiotonic Agents/pharmacokinetics Cyclosporine/pharmacokinetics Dexamethasone/pharmacokinetics Digoxin/pharmacokinetics Glucocorticoids/pharmacokinetics Humans Immunosuppressive Agents/pharmacokinetics Male Mice Morphine/pharmacokinetics Swine Tissue Distribution
Chemicals
ATP Binding Cassette Transporter, Subfamily B, Member 1 Cardiotonic Agents Glucocorticoids Immunosuppressive Agents Digoxin Morphine Dexamethasone Cyclosporine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Schinkel A H
The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands.
Wagenaar E
van Deemter L
Mol C A
Borst P
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI118214
Published
1995-10-00
Pages
1698-705
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC185805
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI118214 PMC Full Text View journal details
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