Pharmacokinetics/Pharmacodynamics Core

PK/PD Core Summary The overall aims of this integrated P01 proposal are to advance fundamental understanding and provide clinical translation of oxytocin’s actions in the periphery and in the central nervous system as they relate to sensory processing and recovery from tissue injury, including surgery. The three goals of this program project are 1) to determine oxytocin pharmacokinetics (relationship between dose and concentration) and pharmacodynamics (relationship between concentration and drug effect) in rats and humans, 2) characterize the mechanisms of oxytocin actions on acute pain and sensitization at peripheral and central sites, and 3) determine the central and peripheral actions of oxytocin on recovery after tissue injury (e.g., surgery). Each of these goals is predicated on precise measurement of oxytocin dose and concentration, construction of mathematical models relating blood oxytocin concentration to oxytocin dose and route of delivery, and construction of mathematical models relating oxytocin concentration to drug effect. The first goal comprises measuring oxytocin dose, concentration, and effect, and developing mathematical models of these fundamental relationships. This is the critical analysis that brings new scientific rigor to the second and third aims, because we will use the pharmacokinetic and pharmacodynamic models to give oxytocin in a manner that facilitates rigorous exploration of the dose – concentration – drug response relationship for both acute pain and sensitization (goal 2) and speed of recovery (goal 3) for both peripheral and central sites (differentiated by leveraging differences in peripheral and central pharmacokinetics to target each site experimentally).