Inhibition and induction of drug-metabolizing
enzymes are the most frequent and dangerous drug-drug interactions. They are an important cause of serious adverse events that have often resulted in early termination of drug development or withdrawal of drugs from the market. Management of such interactions by dose adjustment in clinical practice is extremely difficult because of the wide interindividual variability in their magnitude. This review examines the genetic, physiological, and environmental factors responsible for this variability, focusing on an important but so far neglected cause of variability, liver functional status. Clinical studies have shown that
liver disease causes a reduction in the magnitude of interactions due to
enzyme inhibition, which is proportional to the degree of liver function impairment. The effect of
liver dysfunction varies quantitatively according to the nature, reversible or irreversible, of the inhibitory interaction. The magnitude of reversible inhibition is more drastically reduced and virtually vanishes in patients with advanced hepatocellular insufficiency. Two mechanisms, in order of importance, are responsible for this reduction: decreased hepatic uptake of the inhibitory drug and reduced
enzyme expression. The extent of irreversible inhibitory interactions is only partially reduced, as it is only influenced by the decreased expression of the inhibited
enzyme. Thus, for appropriate clinical management of inhibitory drug interactions, both the liver functional status and the mechanism of inhibition must be taken into consideration. Although the inducibility of drug-metabolizing
enzymes in
liver disease has long been studied, very conflicting results have been obtained, mainly because of methodological differences. Taken together, the results of early animal and human studies indicated that enzyme induction is substantially preserved in compensated
liver cirrhosis, whereas no definitive conclusion as to whether it is significantly reduced in the decompensated state of
cirrhosis was provided. Since ethical constraints virtually preclude the possibility of performing methodologically rigorous investigations in patients with severe
liver dysfunction, studies have recently been performed in animals rigorously stratified according to the severity of
liver insufficiency. The results of these studies confirmed that enzyme induction is virtually unaffected in compensated
cirrhosis and indicated that the susceptibility of enzyme induction to severe
liver dysfunction depends on the type of
nuclear receptor involved and also varies among
enzyme isoforms under the transcriptional control of the same
nuclear receptor. These findings make it clear that no general conclusion can be reached from the study of any particular
enzyme and partly explain the conflicting results obtained by previous studies. Since no general guidelines can be provided for the management of drug interactions resulting from enzyme induction, both the effects and the plasma concentration of the induced drug should be strictly monitored. The findings discussed in this review have important methodological implications as they indicate that, contrary to current guidelines, the magnitude of metabolic drug-drug interactions in patients with
liver disease cannot be inferred from studies in healthy subjects.