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Abstract

In pharmaceutical research, in vitro toxicity tests for assessing the potential toxicity of new chemical entities are necessary in early stages of the developmental process, when no information is available about the metabolism or even the target organ toxicity of the compounds to be tested. In vitro specific organ toxicity tests, such as the granulocyte-macrophrage colony-forming unit (CFU-GM) clonogenic assay, are useful tools for predicting the adverse effects of new compounds on the blood-forming system, provided that some reference points are available, e.g. toxicological information about compounds belonging to the same chemical class and structure-activity relationship data

Furthermore, when no information is available about metabolism, the in vitro system should cover as many possibilities as possible, to avoid falsse positive or false negative results. In fact, while many compounds are metabolized to a variety of inactive chemical species, some undergo bioactivation to form more active metabolites. The addition of a metabolic activation system to the CFU-GM assay enables assessment of direct and metabolism-mediated toxicity. The regulatory agencies and industry value the concept of assays performed with and without metabolic activation, since they often have to take decisions about compounds with unknown mechanisms of action. CFU-GM assay, designed in this way, is an example of such a mechanism-naïve assay.

It has been suggested that, for new compounds, metabolites should be generated and tested both in the presence and in the absence of the parent compound itself, to identify the possible contribution of metabolites to the hematotoxicity observed, and to determine whether there is any synergistic or antagonistic effect between metabolites and the parent compound that might affect hematotoxicity in vivo. vo.

Additional information

Authors: DAL NEGRO G, GlaxoSmithKline, Medicines Research Centre, Verona (IT);BONATO M, GlaxoSmithKline, Medicines Research Centre, Verona (IT);GRIBALDO L, JRC, Institute for Health and Consumer Protection, Ispra (IT)
Bibliographic Reference: An article published in: Cell Biology and Toxicology, Vol.17 (2001), pp.95-105
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