Comparison of in vitro and in vivo haemotoxic effects of aminoglutethimide and glutethimide.
The aromatase inhibitor, aminoglutethimide, causes a blood dyscrasia in about 1% of women taking the drug for the treatment of advanced breast cancer. The parent compound, glutethimide, is known not to possess this toxic action. The effect of both drugs on bone (femur) marrow cells of mice and rats was examined by means of standard methods for the colony forming assay for granulocyte-macrophage (GM-CFC) and erythroid cells (CFU-E). There were no significant effects on the cell colonies up to drug concentrations of at least 10 mug/ml. However, above this level concentration-dependent effects were observed. For mouse GM-CFC, 50 and 30% of the cell colonies died when incubated with glutethimide (33 mug/ml) and aminoglutethimide (100 mug/ml), respectively. Similar results for the two drugs were obtained with the mouse CFU-E and with both cell types from the rat. The results indicate that the inhibitory effects were most likely to be non-specific. For the in vivo study, glutethimide and aminoglutethimide were given orally (50 mg/kg, daily). After 3 wk of this regimen in mice, there was a significant fall (about 50%) in both white blood cell and platelet counts. This is similar to the blood picture changes induced by aminoglutethimide in women. No haematological effects were observed in rats receiving this drug and glutethimide was without effect in either species. Thus, the toxic effects of aminoglutethimide appear to be more selective in vivo than in vitro. It is proposed that N-hydroxylation of aminoglutethimide, which proceeds in mouse and man but not rat, is an important step in the toxic mechanism. Overall the results indicate that the in vitro assessment used in this study was not a suitable predictor of the in vivo haemotoxic effects of aminoglutethimide.
Ali
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Welsh School of Pharmacy, University of Wales College of Cardiff, PO Box 13, Cardiff CF1 3XF, UK.
Khalaf
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Nicholls
P J
PJ
Poole
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A