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.

Effect of Clozapine and Olanzapine on Neutrophil Kinetics: Implications for Drug-Induced Agranulocytosis

“…This discrepancy could involve differences in the covalent binding of the reactive metabolite, or it could be totally independent of reactive metabolite formation. Together with the finding that other drugs that cause agranulocytosis also cause neutrophilia in rats, specifically aminoglutethimide and amodiaquine (unpublished observation), this suggests that the ability of a drug to induce neutrophilia may represent a biomarker of agranulocytosis risk. The accompanying article investigates the effects of clozapine on bone marrow and inflammatory markers in more detail.…”

“…8 We found that clozapine also causes an increase in the release of neutrophils from the bone marrow and total neutrophil count in rabbits as well as a shortened neutrophil half-life. 9 An increase in neutrophils has also been observed in rats treated with aminoglutethimide, 10 which is also associated with a relatively high risk of drug-induced agranulocytosis. This suggests that these early changes in neutrophil kinetics could be a biomarker to predict the risk that a drug would cause agranulocytosis.…”

Metal-Free, Redox-Neutral, Site-Selective Access to Heteroarylamine via Direct Radical–Radical Cross-Coupling Powered by Visible Light Photocatalysis

“…Considering 59% of small-molecule pharmaceuticals containing at least one N -heterocycle, the late-stage decorations of bioactive compounds were further evaluated. As shown in Scheme , aminoglutethimide, a steroidogenesis inhibitor, used in the treatment of Cushing’s syndrome, could be selectively inserted in an isoquinoline fragment to give product 81c in 53% yield. 4-Aminophenyl- d -galactopyranoside, a biologically relevant glycoside, afforded the desired product in 35% yield ( 82c ).…”