Pharmacokinetics at the Interface Between Pharmacology and Physiology
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 Vmax and Km 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.
KeywordsToxicity Carbohydrate Glutathione Aspirin Glycine
Unable to display preview. Download preview PDF.
- 7.J.T. Slattery and G. Levy, Acetaminophen kinetics in acutely poisoned patients, Clin. Pharmacol. Ther. 25: 185–195 (1979).Google Scholar
- 13.J.H. Lin and G. Levy, Effect of inorganic sulfate concentration on kinetics of conjugation of acetaminophen with sulfate by isolated rat hepatocytes, to be published.Google Scholar
- 15.J.H. Lin, R.E. Galinsky and G. Levy, Availability of endogenous inorganic sulfate for conjugation during acetaminophen- induced sulfate depletion in rats, to be published.Google Scholar
- 16.J.H. Lin and G. Levy, manuscript in preparation.Google Scholar