Modulation of P-glycoprotein (Pgp)-mediated transport has significant pharmacokinetic implications for Pgp substrates. Pharmacokinetic alterations may be at the systemic (blood concentrations), regional (organ or tissue concentrations), or local (intracellular concentrations) level. Regardless of the particular location of Pgp modulation, changes in substrate pharmacokinetics will have the potential to alter the magnitude and duration of pharmacologic effect (pharmacodynamics). It is important to understand each of the aspects of Pgp modulation for a given Pgp substrate in order to predict the degree to which Pgp modulation may affect that substrate, to minimize untoward effects associated with that modulation, or to exploit that modulation for specific therapeutic advantage.