Drug-cytokine interactions: mechanisms and clinical implications

The potential for certain cytokines to alter cytochrome P450-mediated drug metabolism was first described over 20 years ago. Since that time, a number of in vitro studies in a variety of models have confirmed those observations and evaluated the possible mechanisms. Although the actual mechanism(s) remains unknown, several potential theories have been proposed, including the inhibition of mRNA transcription, increased haem oxygenase activity, increased xanthine oxidase activity and the induction of killer cells cytotoxic to liver cells containing cytochrome P450. Clinical data regarding drug-cytokine interactions are currently limited to the results of studies with small patient numbers and case reports. In addition, the results of different reports are often conflicting. Some clinical studies have reported associations between exogenous or endogenous cytokines and alterations in concomitantly administered drugs, whereas others have reported a lack of effect. Differences in cytokine dosages, route of administration, time course of therapy, sample collection times and patient variability are all likely to account for the varied results. In this rapidly expanding field, additional research will better define the mechanisms of these interactions and their clinical implications.