Transport by P-glycoprotein (P-gp) is an important determinant of disposition for numerous pharmacological agents. A significant body of evidence has shown that decreases in P-gp activity can increase drug absorption from the GI tract, decrease drug/metabolite excretion in the liver and/or kidney, and enhance distribution of parent drug/active metabolites to target organs (e.g., the CNS) or pharmacologically relevant intracellular sites (e.g., leukocytes). Although the potential for induction of P-gp is well documented in the cancer chemotherapy literature, the implications of P-gp induction on the systemic disposition and pharmacological activity of P-gp substrates has yet to be addressed. Recent work in this laboratory has demonstrated that morphine is a substrate for P-gp-mediated transport, that alterations in P-gp activity influence morphine disposition and action and that morphine administration in vivo increases the P-gp content in rat brain. These observations are particularly important from a clinical perspective because of the key role of morphine in management of pain associated with cancer and other diseases requiring chronic analgesia. Therapeutic agents (e.g., anticancer drugs) that increase P-gp activity may decrease the efficacy of morphine in these patients. Conversely, induction of P-gp by morphine may limit the activity of other P-gp substrates. The long term objective of this research program is to explore the hypothesis that inducers of P-gp cause clinically relevant alterations in the disposition and action of P-gp substrates. The proposed project will utilize a multi-experimental approach to address the hypotheses that: 1) extent of P-gp induction in specific organs is a function of inducer potency and inducer concentration, 2) perturbations in the kinetics of a P-gp substrate can be predicted based on the degree of P-gp induction in organs/tissues, and 3) P-gp induction in humans can result in clinically significant alterations in the systemic disposition and action of P-gp substrates. In addressing these hypotheses, P-gp induction will be assessed in vitro in cultured hepatocytes (rat and human) and in vivo in selected organs, the impact of P-gp induction on drug disposition will be evaluated in isolated organ systems, and the implications of P-gp induction on systemic pharmacokinetics and pharmacodynamics will be examined in rats and humans. The potential importance of this research becomes apparent when one considers the number of therapeutic agents that are substrates of P-gp, the location of P-gp in organs of kinetic/dynamic importance, and the likelihood that numerous therapeutic, dietary, and environmental agents may modulate the activity of P-gp.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061191-04
Application #
6707536
Study Section
Special Emphasis Panel (ZRG1-PTHA (04))
Program Officer
Okita, Richard T
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$231,164
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Padowski, Jeannie M; Pollack, Gary M (2012) Influence of enterohepatic recycling on the time course of brain-to-blood partitioning of valproic acid in rats. Drug Metab Dispos 40:1846-53
Padowski, Jeannie M; Pollack, Gary M (2011) The influence of distributional kinetics into a peripheral compartment on the pharmacokinetics of substrate partitioning between blood and brain tissue. J Pharmacokinet Pharmacodyn 38:743-67
Padowski, Jeannie M; Pollack, Gary M (2011) Influence of time to achieve substrate distribution equilibrium between brain tissue and blood on quantitation of the blood-brain barrier P-glycoprotein effect. Brain Res 1426:1-17
Padowski, Jeannie M; Pollack, Gary M (2010) Examination of the ability of the nasal administration route to confer a brain exposure advantage for three chemical inhibitors of P-glycoprotein. J Pharm Sci 99:3226-33
Zhao, Rong; Raub, Thomas J; Sawada, Geri A et al. (2009) Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood-brain barrier. Drug Metab Dispos 37:1251-8
Zhao, Rong; Pollack, Gary M (2009) Regional differences in capillary density, perfusion rate, and P-glycoprotein activity: a quantitative analysis of regional drug exposure in the brain. Biochem Pharmacol 78:1052-9
Zhao, Rong; Kalvass, J Cory; Pollack, Gary M (2009) Assessment of blood-brain barrier permeability using the in situ mouse brain perfusion technique. Pharm Res 26:1657-64
Zhao, Rong; Kalvass, J Cory; Yanni, Souzan B et al. (2009) Fexofenadine brain exposure and the influence of blood-brain barrier P-glycoprotein after fexofenadine and terfenadine administration. Drug Metab Dispos 37:529-35
Dumas, Emily O; Pollack, Gary M (2008) Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J 10:537-51
Kalvass, J Cory; Olson, Emily R; Cassidy, Michael P et al. (2007) Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther 323:346-55

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