Current understanding of the mechanisms of idiosyncratic drug-induced agranulocytosis

Abstract

Introduction: Idiosyncratic drug-induced agranulocytosis (IDIAG) is a life-threatening adverse reaction characterized by an absolute neutrophil count < 500 cells/μl of blood. It shares many of the characteristics of other idiosyncratic drug reactions (IDRs), and this presumably reflects mechanistic similarities.

Areas covered: This review describes the evidence for mechanistic hypotheses of IDIAG and new hypotheses are explored.

Expert opinion: The characteristics of IDIAG are most consistent with an immune mechanism. Where genetic studies have been done, the genes associated with an increased risk of IDIAG are either human leukocyte antigen genes or other genes associated with the immune response, which provides further evidence for an immune mechanism. There is evidence that the immune response leading to most IDRs is triggered by reactive metabolites of the offending drug, and most drugs that are associated with IDIAG are either known to be oxidized to a reactive metabolite by neutrophils or have a functional group that has the potential to be easily oxidized to a reactive metabolite. There is new evidence that drugs that cause IDRs including IDIAG can activate inflammasomes. Thus, the ability of a drug to be oxidized to a reactive metabolite by neutrophils and to activate inflammasomes may be useful biomarkers to predict IDIAG risk.

Keywords:

• adverse drug reactions
• danger hypothesis
• drug-induced agranulocytosis
• hapten hypothesis
• idiosyncratic drug reactions
• inflammasome
• myeloperoxidase
• neutrophil
• reactive metabolites

Declaration of interest

This work was supported by grants from the Canadian Institutes for Health Research. J Uetrecht holds the Canada Research Chair in Adverse Drug Reactions. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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