Do my compounds generate reactive metabolites ?

Formation of reactive metabolites has been implicated in a range of clinical toxicities and is thought to be responsible for the majority of  'idiosyncratic' toxic responses to drugs. Generation of reactive metabolites has also been implicated in covalent protein binding leading to immune mediated toxicity or adverse drug-drug interactions. Assessment of the potential reactive metabolite formation is therefore important in the early ADMET characterisation of compounds to help design preclinical and clinical studies.

The CXR approach

Initial screens would incubate test compounds with heptaocytes from a range of species including human to determine the hepatoxicity of any phase 1 or phase 2 metabolites generated. The mechanism of any toxicity would then be further investigated by measuring glutathione depletion which provides an indication of the formation of reactive metaboltites in that species. This comparison would provide information about the potential for reactive metabolite fomration in both test species and man. Further work can then investigate whether covalent protein binding occurs using radiolabeled test compounds, and can explore if this is associated with irreversible inhibition of CYP enzymes through mechanistic inhibtion studies. This staged appraoch can cost-effectively determine the potential concern for preclinical and clinical safety studies.