PHARMACOKINETICS OF 4-HYDROXYANDROSTENEDIONE IN MAN AFTER INTRAMUSCULAR INJECTION OF DIFFERENT FORMULATIONS AND THE EFFECT OF THIS DRUG ON PLASMA AROMATIZABLE ANDROGENS AND 17-BETA-ESTRADIOL CONCENTRATIONS

Pharmacokinetics of 4-hydroxyandrostenedione (4-OHA), a potent aromatase inhibitor under investigation for treatment of postmenopausal breast cancer, were studied using two formulations with different particle sizes of 4.2 and 8.0 mum, respectively. A single 250 mg dose of 4-OHA of each of the two formulations was administered in two different periods to six healthy male volunteers and blood samples were collected for up to 14 days. 4-OHA plasma levels were determined using the isotope dilution mass spectrometry method. Comparison of the pharmacokinetic profiles of the two formulations did not show any statistically significant difference, even though the 4.2 mum particle size gave apparently higher levels at 24 h. Using this formulation, the effects of 4-OHA on the plasma levels of aromatizable androgens (testosterone and androstenedione) and 17beta-estradiol were studied. An isotope dilution mass spectrometry method was developed for the simultaneous quantitative determination of these steroids in human plasma. The analysis of plasma samples showed a significant reduction of plasma estradiol concentrations (50%) which coincided with the maximum concentration peak of the inhibitor, whereas no significant changes in androgen levels were observed.