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Mechanisms of neutropenia: The role of Neutrophil‐specific pathways of drug metabolism
Author(s) -
Uetrecht J. P.,
Spielberg S. P.
Publication year - 1993
Publication title -
pharmacoepidemiology and drug safety
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.023
H-Index - 96
eISSN - 1099-1557
pISSN - 1053-8569
DOI - 10.1002/pds.2630020708
Subject(s) - medicine , myeloperoxidase , drug metabolism , neutropenia , drug , metabolite , pharmacology , inflammation , immunology , immune system , pathogenesis , metabolism , toxicity
Neutrophils are capable of metabolizing drugs by oxidative pathways based on myeloperoxidase‐generated hypochlorous acid. The metabolites formed may be similar or quite different from those generated by cytochrome P‐450 metabolism. Some metabolites are unstable, reactive products capable of covalently binding to cell macromolecules with resultant cytotoxicity and/or neoantigen formation with subsequent immunologic response. It is likely that such metabolites play a role in the pathogenesis of drug‐induced neutropenia. The pathogenic role of antibodies expressed to neoantigens and their utility as biologic markers of an impending ADR remain to be elucidated. The requirement for activation of cells to express oxidative metabolism raises important issues with respect to role of co‐factors such as inflammation and infection in predisposing patients to ADRs. Even for drugs with relatively high incidences of agranulocytosis (1–2 per cent), the vast majority of patients do not have an ADR. Issues of subpopulation risk such as pharmacogenetic differences in drug metabolite detoxification and differences in immune response which may modify the likelihood of an ADR are subjects for future investigation.