Clearing the MIST (metabolites in safety testing) of time: The impact of duration of administration on drug metabolite toxicity

The importance of mass and concentration. rather than percentage. in determining the safety of risk of metabolites has been the subject of recent scholarship. These studies have not examined the dimension of time as represented by the duration of exposure to the chemical. Reviewing a wide range of clinical information duration of exposure is not a pivotal factor for most types of toxicity, particularly those classified as types A, B or C where concentration and mass are the primary considerations. For instance in idiosyncratic toxicity, classified as type B, where a reactive metabolite is implicated and an immune response is generally required, toxicity can occur early in treatment (1 week to 1 month after starting therapy). In contrast to this type D toxicity in particular carcinogenicity requires that duration of exposure is taken into consideration alongside mass and dose and should be considered the most critical factor. To elicit a response known human carcinogens need a duration of exposure of many years combined with an induction/latency period also measured in years. The perceived risk of a unique human metabolite as a potential health risk by carcinogenesis becomes exceedingly low when the time scale for effect is compared with the age of patients undergoing therapy and their duration of treatment. (C) 2008 Elsevier Ireland Ltd. All rights reserved.