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Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.
Schinkel AH,
Smit JJ,
van Tellingen O,
Beijnen JH,
Wagenaar E,
van Deemter L,
Mol CA,
van der Valk MA,
Robanus-Maandag EC,
te Riele HP, et al.
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.
We have generated mice homozygous for a disruption of the mdr1a (also called mdr3) gene, encoding a drug-transporting P-glycoprotein. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectin (100-fold) and to the carcinostatic drug vinblastine (3-fold). By comparison of mdr1a (+/+) and (-/-) mice, we found that the mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many tissues (especially in brain) and in decreased drug elimination. Our findings explain some of the side effects in patients treated with a combination of carcinostatics and P-glycoprotein inhibitors and indicate that these inhibitors might be useful in selectively enhancing the access of a range of drugs to the brain.
PMID: 7910522 [PubMed - indexed for MEDLINE]
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Cited by 73 PubMed Central articles
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ADDME - Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective.
Tsaioun K, Bottlaender M, Mabondzo A, Alzheimer's Drug Discovery Foundation.
BMC Neurol. 2009 Jun 12; 9 Suppl 1:S1. Epub 2009 Jun 12.
[BMC Neurol. 2009]
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Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination.
Fenneteau F, Turgeon J, Couture L, Michaud V, Li J, Nekka F.
Theor Biol Med Model. 2009 Jan 15; 6:2. Epub 2009 Jan 15.
[Theor Biol Med Model. 2009]
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Characterization of intestinal inflammation and identification of related gene expression changes in mdr1a(-/-) mice.
Dommels YE, Butts CA, Zhu S, Davy M, Martell S, Hedderley D, Barnett MP, McNabb WC, Roy NC.
Genes Nutr. 2007 Nov; 2(2):209-23. Epub 2007 Sep 27.
[Genes Nutr. 2007]
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Patient Drug Information
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Vinblastine (Velban® )
Your doctor has ordered the drug vinblastine to help treat your illness. The drug is given by injection into a vein.
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Ivermectin (Stromectol® )
Ivermectin is used to treat strongyloidiasis (threadworm; infection with a type of roundworm that enters the body through the skin, moves through the airways and lives in the intestines). Ivermectin is also used to contr...