title: Metabolism of vesnarinone by activated neutrophils: implications for vesnarinone-induced agranulocytosis.
abstract: Vesnarinone is an important new drug that significantly decreases mortality rates in severe congestive heart failure; however, its use is associated with a relatively high incidence (approximately 1%) of agranulocytosis. The authors studied its metabolism by activated neutrophils, the target for this toxicity, and evidence pointed to a pathway that involved a reactive iminium ion. Hydrolysis of the iminium ion led to a reactive quinone imine. The same pathway was observed with a combination of myeloperoxidase/hydrogen peroxide/chloride, the major oxidizing system of neutrophils, or hypochlorous acid, which is generated by this system. Activation of the neutrophils could be achieved by phorbol ester or by influenza vaccine and there is evidence to suggest that the administration of influenza vaccine during vesnarinone therapy may increase the risk of agranulocytosis. Incubation of radiolabeled vesnarinone with activated neutrophils led to covalent binding of almost 5% of the drug to the cells. Both the iminium ion and quinone imine generated by hypochlorous acid could be trapped with glutathione. It was proposed that these reactive metabolites, generated by neutrophils or neutrophil precursors in the bone marrow, may be responsible for the vesnarinone-induced agranulocytosis. Factors such as infection or vaccination that activate neutrophils may increase the risk of agranulocytosis.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Uetrecht
authors.forename: N
authors.initials: N
authors.lastname: Zahid
authors.forename: D
authors.initials: D
authors.lastname: Whitfield
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced*; D000418:Albumins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007252:Influenza Vaccines / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines; D011804:Quinolines / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D000418:Albumins; D002316:Cardiotonic Agents; D007252:Influenza Vaccines; D011719:Pyrazines; D011804:Quinolines; C041667:vesnarinone; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D009195:Peroxidase; D005978:Glutathione