Evidence strongly suggests that many adverse drug reactions, including 
idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain 
functional groups, which are readily oxidized to reactive metabolites, are 
associated with a high incidence of adverse reactions. Most drugs can probably 
form reactive metabolites, but a simple comparison of covalent binding in vitro 
is unlikely to provide an accurate indication of the relative risk of a drug 
causing an idiosyncratic reaction because it does not provide an indication of 
how efficiently the metabolite is detoxified in vivo. In addition, the incidence 
and nature of adverse reactions associated with a given drug is probably 
determined in large measure by the location of reactive metabolite formation, as 
well as the chemical reactivity of the reactive metabolite. Such factors will 
determine which macromolecules the metabolites will bind to, and it is known 
that covalent binding to some proteins, such as those in the leukocyte membrane, 
is much more likely to lead to an immune-mediated reaction or other type of 
toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely 
and could lead to adverse reactions in almost any organ; however, most reactive 
metabolites have a short biological half-life, and although small amounts may 
escape the organ where they are formed, these metabolites are unlikely to reach 
sufficient concentrations to cause toxicity in other organs. Many idiosyncratic 
drug reactions involve leukocytes, especially agranulocytosis and drug-induced 
lupus. We and others have demonstrated that drugs can be metabolized by 
activated neutrophils and monocytes to reactive metabolites. The major reaction 
appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous 
acid is quite reactive, and therefore it is likely that many other drugs will be 
found that are metabolized by activated leukocytes. Some neutrophil precursors 
contain myeloperoxidase and the NADPH oxidase system, and it is likely that 
these cells can also oxidize drugs. Therefore, although there is no direct 
evidence, it is reasonable to speculate that reactive metabolites generated by 
activated leukocytes, or neutrophil precursors in the bone marrow, could be 
responsible for drug-induced agranulocytosis and aplastic anemia. This could 
involve direct toxicity or an immune-mediated reaction. These mechanisms are not 
mutually exclusive, and it may be that both mechanisms contribute to the 
toxicity, even in the same patient. In the case of drug-induced lupus, a 
prevalent hypothesis for lupus involves modification of class II MHC 
antigens.(ABSTRACT TRUNCATED AT 400 WORDS)