The importance of tissue distribution in pharmacokinetics

The concentration of a drug at its site of action will be affected by the ability of the drug to distribute to and pass through various membranes and tissues. Mechanisms of drug distribution are summarized in this paper and include the differences between intracellular and extracellular pH,active transport systems for drugs, distribution of drugs between fat and water in adipose tissues, the reversible binding of drugs to phospholipids and to various macromolecules including proteins, nucleic acid, and melanin. These mechanisms usually tend to decrease the concentration of unbound drugs at their sites of action, but usually not to the extent one would predict on the basis of in vitrobinding studies. The effects of drug distribution in altering the biological half-lives of drugs in the body are discussed as well as the interrelationship between the kinetic volumes of distribution for drugs and blood flow rates through the organs that eliminate these drugs. These concepts are illustrated for corticosterone levels following intravenous bolus injections and infusions into rats.This paper was presented at the Conference on Pharmacology and Pharmacokinetics: Problems and Perspectives, October 30–November 1, 1972, at the Fogarty International Center, National institutes of Health, Bethesda, Maryland. This paper, in a slightly different format, will be published in the Proceedings of the Conference by Plenum Press, New York.