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9919307 
Journal Article 
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 
1994 
Yes 
Cell
ISSN: 0092-8674
EISSN: 1097-4172 
77 
4 
491-502 
English 
7910522 
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. 
ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier/drug effects/physiology; Capillaries/chemistry; Carrier Proteins/analysis/genetics/physiology; Drug Resistance/genetics; Epithelial Cells; Intestine, Small/chemistry; Ivermectin/blood/pharmacokinetics/toxicity; Membrane Glycoproteins/analysis/genetics/physiology; Mice, Knockout/genetics; Mutagenesis, Insertional; RNA, Messenger/analysis; Tissue Distribution; Vinblastine/pharmacokinetics/toxicity