The investigators have demonstrated that fentanyl and verapamil are substrates of two distinct transporters at the blood-brain barrier: an efflux transporter, P-glycoprotein (P-gp), and an unidentified uptake transporter. The proposed work will study the pharmacology of these endothelial mechanisms. Kinetic studies using cultured endothelial cells derived from lung and brain will investigate the extent to which the partitioning of opioid anesthetic drugs into or away from these tissues is mediated by drug transporters, and what drugs or factors influence them. Isolated perfused rat lung studies will be conducted to determine the contribution of the lung tissue matrix to the pharmacokinetics of drug distribution, and to further validate models of pulmonary uptake developed as part of the in vivo recirculatory pharmacokinetic models. Pharmacokinetic-pharmacodynamic studies of CNS effects of synthetic opioid drugs will be performed in an in vivo rat EEG paradigm and correlated to analgesia. Treatment will consist of blockade of either endothelial drug uptake or efflux functions. These experiments will describe any changes in the speed of onset and offset of drug effect and the sensitivity of the brain to opioid due to changes in drug transporter function. These experiments are designed to differentiate changes in pharmacokinetics produced by transporter blockade in the body as a whole (specifically the lung) from changes at the brain effect site.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Cole, Alison E
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University of Colorado Denver
Schools of Medicine
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Elkiweri, Iman A; Zhang, Yan Ling; Christians, Uwe et al. (2009) Competitive substrates for P-glycoprotein and organic anion protein transporters differentially reduce blood organ transport of fentanyl and loperamide: pharmacokinetics and pharmacodynamics in Sprague-Dawley rats. Anesth Analg 108:149-59
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