PHARMACOKINETICS AND PHARMACODYNAMICS OF THE AROMATASE INHIBITOR 3-ETHYL-3-(4-PYRIDYL)PIPERIDINE-2,6-DIONE IN PATIENTS WITH POSTMENOPAUSAL BREAST-CANCER

The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3-4 days, oestradiol levels fell to 31.1% +/- 6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2-mu-g/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates for C(o) (21.7 +/- 1.82-mu-g/ml), K(m) (2.66 +/- 0.68-mu-g/ml) and V(max) (0.86 +/- 0.06-mu-g ml-1 h-1). On subsequent repeated dosing with PyG, both the K(m) (4.31 +/- 0.48-mu-g/ml) and the V(max) (1.83 +/- 0.13-mu-g ml-1 h-1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.