P-glycoprotcin (P-gp), an adenosine 5'-triphosphate (ATP)-binding cassette (ABC) efflux transporter encoded by the multi-drug resistance 1 ( MDR1) gene, has demonstrated clinical and biological relevance in numerous in vitro and in vivo (preclinical and clinical) studies. Modulations of P-gp activity can significantly affect the absorption, distribution, metabolism and excretion (ADME) of drugs, with the effect being most pronounced on the distribution of drugs into the brain across the blood brain barrier (BBB). Therefore, P-gp based drug interactions at the BBB could significantly increase the CNS toxicity or efficacy of drugs. To predict the magnitude of P-gp based drug interaction at the human BBB, rodents and in vitro studies are routinely utilized as preclinical models. The studies proposed here will assess the accuracy of these models to predict P-gp based drug interaction at the human BBB. To test this hypothesis, we determine if in vivo P-gp based drug interactions at the rat BBB correlated to in vitro studies using the LLCPK1-MDR1 cells. They were. Then, using these in vitro and in vivo rat data, we predicted the magnitudes of P-gp based drug interaction at the human BBB for the human clinical data. The data obtained to date indicated an excellent agreement from in vitro to in vivo rat BBB to in vivo human BBB P-gp based drug interactions.
|Advisor:||Unadkat, Jashvant D.|
|School:||University of Washington|
|School Location:||United States -- Washington|
|Source:||DAI-B 73/02, Dissertation Abstracts International|
|Subjects:||Neurosciences, Cellular biology, Pharmacy sciences|
|Keywords:||Blood-brain barrier, Drug-drug interactions, P-glycoprotein|
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