The Pharmacodynamic Inhibition of Estrogen Synthesis by Fadrozole, an Aromatase Inhibitor, and Its Pharmacokinetic Disposition

G. M. Kochak, S. Mangat, M. T. Mulagha, E. A. Entwistle, R. J. Santen, A. Lipton, L. Demers

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Abstract

In this dose-ranging phase I study, the relationship between in vivo androgen to estrogen conversion kinetics and plasma concentrations of fadrozole was investigated in postmenopausal women receiving therapy with this aromatase inhibitor. Patients received ascending doses, ranging from 0.3–8 mg fadrozole twice daily, each for a period of 2 weeks. Drug kinetics and endocrine effects were evaluated specifically for the 2- and 8-mg twice daily treatment regimens. The in vivo activity of the drug was demonstrated by the suppression of estrone and estradiol biosynthesis from testosterone and androstenedione, respectively. The drug inhibitory constant, K1, for the estrone synthetic pathway, was 3.0 ng/mL (13.4 nmol/L) and was of similar magnitude as that determined under in vitro conditions. The K1 for the estradiol synthetic pathway was 5.3 ng/mL (23.7 nmol/L). The disparity between K1 values may indicate that the two pathways are not equivalent in terms of their inhibition by fadrozole. Pharmacokinetic data demonstrated that the drug was rapidly absorbed after oral dosing, with peak plasma concentrations achieved in median times of 1 and 2 h, respectively, for the 2- and 8-mg twice daily treatment regimens. The average half-life and oral clearance values were 10.5 h and 621 mL/min, respectively. Oral clearance was independent of dose.

Original languageEnglish (US)
Pages (from-to)1349-1355
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume71
Issue number5
DOIs
StatePublished - Nov 1990

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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