The effects of impaired renal function on drug disposition and responsiveness have generally been examined with respect to alterations in the behaviour of unchanged drug. For drugs which are extensively excreted via the kidneys various approaches have been applied to modify dosage regimens in order to optimise drug concentration-time profiles. However, it is now recognised that even if urinary excretion is not an important route of drug elimination, renal failure may affect the body's handling of a drug and its clinical effects. This may occur by the greater than normal accumulation of drug metabolites which are predominantly excreted in the urine, leading to a situation analogous to coadministration of another drug and the possible sequelae of a drug-drug interaction.The accumulation of pharmacologically and/or toxicologically active metabolites in renal failure occurs in several instances and can significantly alter clinical effects at the pharmacodynamic level. Accumulated inactive metabolites, especially those formed by conjugation with glucuronic acid, may also lead to a change in drug action by way of regeneration of the parent drug. This in turn may alter the disposition characteristics of the precursor drug even though urinary excretion is not an important pathway of elimination in individuals with normal renal function.It is also possible that metabolites may have a direct dispositional interaction with the parent drug. This would most likely occur through competition for non-linear processes such as plasma and tissue binding, active transport and enzyme-mediated reactions. The degree of such inhibition would be dependent on the relative affinities and concentrations of the interacting compounds, and thus renal failure could exaggerate this type of phenomenon. However, these types of interactions are not well substantiated, probably because of their complexity and subtlety.The higher than normal accumulation of metabolites in renal failure may also affect diagnostic procedures either directly or indirectly. For example, the metabolite may interfere with the analysis of an endogenous compound used for diagnostic purposes. Alternatively, the disposition of the drug may be used in a diagnostic fashion, as occurs with the determination of drug acetylation phenotype. In the latter instance, methodologies based on parent drug-metabolite ratios in the plasma and/or urine may well be misleading when applied to patients with impaired renal function.