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.
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