Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications

The volume of distribution of a drug (Vd) is a useful pharmacokinetic parameter for relating drug concentration in the plasma to the total amount of drug in the body. Disease-induced changes in Vd may well result in a change in the therapeutic or toxic significance of a given plasma level. For the different factors under consideration, especially plasma protein binding, the weight and the age of the patient plays an important role. Plasma binding of many drugs is lower in patients with renal or liver disease and binding capacity can be decreased in neonates and elderly individuals. Since the heart, liver and kidney are the major organs determining the distribution and elimination of drugs, it is not surprising that alterations in their function will influence the pharmacokinetic properties of drugs. When comparing the Vd in different groups of patients one should use Vd(ss), since this is the only meaningful term as it is independent from elimination processes. Drugs which are strongly bound to plasma constituents (e.g. phenytoin, diazepam) demonstrate an increased Vd in patients with liver or kidney disease, since plasma binding is lowered. A reduced Vd seems to be a general phenomenon associated with renal failure and pronounced changes are most likely for drugs that are eliminated by a renal excretory mechanism (e.g. digoxin). From these disease-induced changes in Vd it follows, that plasma level monitoring should be done more extensively in patients with kidney, liver or heart disease and that arbitrary dosing regimens are only of limited value in these patients. It is also recommended that dosage should be adjusted according to the severity of the disease.