Theoretic aspects of pharmacokinetic drug interactions

Abstract

Various nutritional and environmental factors are known to alter the rates at which drugs are absorbed, distributed, metabolized, and eliminated from the body. Some of these factors may exert their effects by changing gastrointestinal motility, blood flow rates through various organs, the activities of enzymes that catalyze the metabolism of drugs, the reversible binding of drugs to components in blood and other tissues, and the rate of elimination by the kidney. Because these physiologic and biochemical functions are interrelated, however, a given change in anyone of them mayor may not result in significant changes in the concentration of unbound drug at pharmacologic and toxicologic action sites. Indeed, whether the concentration of unbound drug at action sites is significantly changed may also depend on the principle organ of elimination, the route of administration, and the dosage schedule of the drug. In order to illustrate the effects of alterations in blood flow rates, enzyme activity, and reversible binding to blood components on the total body clearance of drugs, mathematical equations were derived for a general pharmacokinetic model that includes elimination of drugs by feces, intestinal mucosa, liver (metabolism and biliary excretion), lung, and kidney. With these equations it is possible to describe the conditions under which a change in the activities of drug‐metabolizing enzymes in a given organ or a change in the reversible binding of drugs to blood components may result in significant changes in the apparent total body clearance of drugs and thus in significant changes in the average steady‐state concentration of unbound drug at action sites after multiple doses. The fact that reversible binding of drugs to blood components may result in either increases or decreases in the half‐life of drugs in the body is noted, and a universally applicable nomogram has been designed to illustrate the conditions under which each of these events will occur.