Reactive intermediates and the pathogenesis of adverse drug reactions: the toxicology perspective

Severe adverse drug responses are infrequent but occasionally serious events that are not readily predictable at the preclinical development level using only non-human or in vitro models. A common characteristic of the more serious toxicities is generation of short-lived and highly reactive electrophilic species in some individuals. The objective here is to review the literature for toxicological mechanisms that underlie known adverse drug reactions and then categorize the biological consequences of reactive chemical intermediates and radicals in terms of human risk factors and known metabolic variables. Xenobiotics described as being associated with rare but potentially serious adverse events affecting liver, skin, or causing blood dyscrasias tend to have three of four essential characteristics, (1) they are capable of forming short-lived reactive intermediates (RI) or free radicals in target tissues under ideal conditions that are distinct from primary metabolic products, (2) these RI escape/overwhelm the detoxification mechanisms associated with the site of origin or form toxic conjugates, (3) the unconjugated RI must either selectively damage critical proteins or other key macromolecules or (4) the RI acts as a hapten and stimulates an immunological (hypersensitivity) response or overcomes tolerance. Some risk factors may increase the probability of susceptibility, but this remains an active area of research. Because of the complexity of the pathogenesis of some injuries and the role of individual factors, no highly predictive in vitro screening methods are available; however, several methods are evolving that may be used to reveal mechanisms of action when a serious adverse effect is encountered.