title: Effect of aminoglutethimide on neutrophils in rats: implications for idiosyncratic drug-induced blood dyscrasias.
abstract: Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyncratic drug-induced agranulocytosis. Although AMG does not cause agranulocytosis in most animals or humans, drugs associated with serious IDRs generally cause a higher incidence of mild reactions that resolve despite continued treatment. Therefore, the effects of AMG on neutrophils and bone marrow in rats were studied to understand the mechanisms of more serious IDRs. An increase in peripheral blood neutrophils occurred as early as 24 h after AMG treatment with minimal changes to the total leukocyte count. Further investigation using 5-bromo-2'-deoxyuridine (BrdU) found an increased release of neutrophils from the bone marrow. Histologically, this corresponded to an increase in myeloid cells in the bone marrow, which was confirmed by differential staining with CD45 and CD71. AMG treatment stimulated an increase in colony forming unit granulocyte-macrophage and colony forming unit granulocyte ex vivo. There was also a marked increase in the number of activated neutrophils in the circulation expressing the extravasation marker CD62L. These findings indicate that AMG affects neutrophil production, release, and function. Similar effects on neutrophil kinetics in clozapine-treated rats have previously been found, and transient neutrophilia has been observed in patients taking other drugs associated with idiosyncratic agranulocytosis; therefore, the changes observed with AMG may be biomarkers to predict the risk that a drug will cause agranulocytosis.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 3M2.
authors.forename: Winnie
authors.initials: W
authors.lastname: Ng
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000616:Aminoglutethimide / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D019041:L-Selectin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011990:Receptors, Transferrin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D016207:Cytokines; D011990:Receptors, Transferrin; D000616:Aminoglutethimide; D019041:L-Selectin; D017493:Leukocyte Common Antigens