DISRUPTION OF THE MOUSE MDR1A P-GLYCOPROTEIN GENE LEADS TO A DEFICIENCY IN THE BLOOD-BRAIN-BARRIER AND TO INCREASED SENSITIVITY TO DRUGS

We have generated mice homozygous for a disruption of the mdr1a (also called mdr3) gene, encoding a drug-transporting P-glycoprotein. The mi ce were viable and fertile and appeared phenotypically normal, but the y displayed an increased sensitivity to the centrally neurotoxic pesti cide ivermectin (100-fold) and to the carcinostatic drug vinblastine ( 3-fold). By comparison of mdr1a (+/+) and (-/-) mice, we found that th e mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many t issues (especially in brain) and in decreased drug elimination. Our fi ndings explain some of the side effects in patients treated with a com bination of carcinostatics and P-glycoprotein inhibitors and indicate that these inhibitors might be useful in selectively enhancing the acc ess of a range of drugs to the brain.