Pharmacokinetics at the Interface Between Pharmacology and Physiology

Abstract

It is customary to consider the activity of enzyme or transport systems or the perfusion rate of organs as rate determining or limiting in the elimination of drugs from the body. However, some drug conjugation processes are limited by the availability of an endogenous cosubstrate. A comprehensive characterization of the pharmacokinetics of drugs that are affected by limited cosubstrate availability requires models that include representation of all processes affecting the concentration-time profile of the co substrate. The latter may be subject to a number of physiologic controls that facilitate homeostasis, including feedback control of formation rate and concentration-dependent renal clearance. These processes can be affected by pathophysiologic variables, and their effects on drug disposition can be both dose- and time-dependent. Additional complexity of the system may arise from drug and endogenous cosubstrate concentration-dependent changes in apparent V_max and K_m of drug biotransformation processes that are bisubstrate reactions. The pharmacokinetics of these complex nonlinear systems have important pharmacologic implications and exemplify the interrelationship between metabolic processes involving both exogenous and endogenous substrates. Thus, drug biotransformation processes that are associated with and affected by depletion of an endogenous cosubstrate illustrate the interdigitation of pharmacology and physiology and emphasize the need for appreciating the role of both pharmacologic and physiologic factors in pharmacokinetic research.