N-oxidation of drugs associated with idiosyncratic drug reactions

Circumstantial evidence strongly suggests that most idiosyncratic drug reactions are due to reactive metabolites of drugs rather than due to the drugs themselves. Many of the drugs that are associated with idiosyncratic drug reactions contain nitrogen. There are many possible reasons for this association. One is simply that many drugs, especially CNS active drugs, contain nitrogen. In addition, nitrogen is relatively easy to oxidize because of its lone pair of electrons and many nitrogen-containing compounds readily undergo redox cycling, which can generate reactive oxygen species. There are several nitrogen-containing function groups that are especially associated with adverse reactions. These include aromatic amines, nitro compounds (nitro compounds are reduced to the same reactive intermediates as are formed by oxidation of the corresponding aromatic amine), hydrazines and compounds that can be oxidized to iminoquinone and related compounds. A greater attention to the issue of reactive metabolites during drug development would likely lead to safer drugs; however, not all drugs that form reactive metabolites are associated with a high incidence of idiosyncratic drug reactions. In addition to the presence of such a group, other factors, such as dose and electron density of the compound, appear to play a role in whether the drug containing such functional groups will be associated with a relatively high incidence of idiosyncratic drug reactions.