Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs

AH Schinkel, JJM Smit, O van Tellingen, JH Beijnen… - Cell, 1994 - cell.com
AH Schinkel, JJM Smit, O van Tellingen, JH Beijnen, E Wagenaar, L Van Deemter, C Mol…
Cell, 1994cell.com
We have generated mice homozygous for a disruption of the mdrfa (also called mdr3) gene,
encoding a drugtransporting P-glycoprotein. The mice were viable and fertile and appeared
phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic
pesticide ivermectln (lOO-fold) and to the carcinostatic drug vinblastine@-fold). By
comparison of mdrla (+ I+) and (-/-) mice, we found that the mdrla P-glycoprotein is the major
P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels …
Summary
We have generated mice homozygous for a disruption of the mdrfa (also called mdr3) gene, encoding a drugtransporting P-glycoprotein. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectln (lOO-fold) and to the carcinostatic drug vinblastine@-fold). By comparison of mdrla (+ I+) and (-/-) mice, we found that the mdrla 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.
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