Idiosyncratic Drug Reactions: A 35-Year Chemical Research in Toxicology Perspective

When Larry Marnett founded Chemical Research in Toxicology, the study of idiosyncratic drug reactions (IDRs) was in its infancy. There was evidence that IDRs involve chemically reactive metabolites, and many of the papers in Chemical Research in Toxicology investigated the bioactivation of drugs. However, it became clear that not all drugs that form reactive metabolites are associated with a high risk of IDRs, and some drugs that do not appear to form reactive metabolites do cause IDRs. Some of the early Chemical Research in Toxicology papers investigated involvement of the adaptive immune system in the mechanism of IDRs, and HLA associations provided strong evidence for an immune mechanism of IDRs. This led to the question of how reactive metabolites might induce an immune response. The classic hapten hypothesis provided an obvious explanation, but a new hypothesis the danger hypothesis, added another dimension. Although there are common features to IDRs, it is becoming increasingly clear that there are also many differences in the mechanisms caused by different drugs. Other pharmacological effects of drugs may also play a role in the mechanism, and that is obviously true of IDRs caused by biological agents. The requirement for specific HLA and T-cell receptors is presumably the major factor that makes IDRs idiosyncratic. However, an innate immune response is required to prime the adaptive immune response. In contrast to the adaptive immune response, the innate immune response is unlikely to be idiosyncratic, and studies of the innate immune response to drugs may provide a much more accurate way to screen drugs for their potential to cause IDRs. For essential drugs that are known to cause IDRs, it may be possible to markedly decrease risk by a slow dose titration to induce immune tolerance. Significant progress has been made in the study of IDRs, but there is still a long way to go.