Drug Metabolism by the Mitochondrial Amidoxime Reducing Component (mARC): Rapid Assay and Identification of New Substrates

For the development of new drugs, the investigation of
their metabolism
is of central importance. In the past, the focus was mostly on the
consideration of established enzymes leading to oxidations such as
cytochrome P450. However, reductive metabolism by the mARC enzyme
system can play an important role in particular for nitrogen containing
functional groups. A rapid test was established to give developers
of new drugs in the preclinical stage the opportunity to test the
metabolism by mARC. To demonstrate the relevance and validity of the
new test system, known and potential substrates were applied to this
new assay. All known substrates could be detected by the system. Furthermore,
several new substrates were found including long-established drugs
such as hydroxyurea and new compounds in development such as epacdadostat.