Disease-induced modifications of drug pharmacokinetics.

This article attempts to help in the understanding of the mechanisms responsible for a modified drug pharmacokinetic profile in disease states. The main factors influencing the fate of the drug as it moves from the site of administration to the sites of elimination are depicted. Changes in absorption kinetics can be due to altered gastrointestinal peristalsis and secretions as well as modifications of splanchnic blood flow. Pathological states may affect the binding of drugs to plasma proteins, mainly human serum albumin and alpha 1 acid glycoprotein. The resulting modifications in the free fraction of the drug can cause a change in the volume of distribution. The distribution can also be influenced by circulatory disorders modifying local blood flows and thus impeding drug entry into the tissues. Many diseases can alter hepatic and/or renal clearance. This is not surprising since the elimination mechanisms are dependent upon many factors such the enzymatic status of the liver, plasma protein binding, and blood flow to both the liver and the kidney. Some examples such as the modification of furosemide pharmacokinetics in acute renal failure, the impaired metabolism of opiate analgesics in hepatic insufficiency, the alterations of the usual disposition process in salicylic acid intoxication, and the influence of cardiac failure upon some drugs pharmacokinetics, have been chosen to illustrate some of the aspects discussed. Some simple rules for making a rational selection of drugs in pathological states are also outlined.