Bioequivalence Studies of Tibolone in Premenopausal Women and Effects on Expression of the Tibolone‐Metabolizing Enzyme AKR1C (Aldo‐Keto Reductase) Family Caused by Estradiol

This study aimed to investigate the bioequivalence of a test formulation of tibolone with the marketed reference formulation in 24 young healthy female volunteers. Tibolone is a synthetic steroid hormone for menopausal women. Volunteers were treated with the 2 formulations of tibolone (total dose of active ingredient 2.5 mg) according to a 2 × 2 crossover design with a 1‐week washout period. Plasma concentrations of 3α‐ and 3β‐hydroxytibolone, which are major metabolites of tibolone, were assayed in timed samples over a 24‐hour period with a validated gas chromatography/mass spectrometry (GC/MS) method that had a lower limit of quantification of 0.5 ng/mL. The reference and test formulations gave a mean 3α‐hydroxytibolone C max of 5.0 and 5.2 ng/mL, respectively, and a mean 3β‐hydroxytibolone C max of 16.4 and 16.5 ng/mL, respectively. The mean AUC t of 3α‐hydroxytibolone was 24.7 and 24.3 ng h/mL, whereas the mean AUC t of 3β‐hydroxytibolone was 57.6 and 54.8 ng h/mL for the test and reference formulations, respectively. The authors did not find significant differences in pharmacokinetic parameters between the 2 formulations, but metabolite formation was different from reports in postmenopausal women. The authors therefore measured the effects of estradiol on the expression of the tibolone‐metabolizing enzymes, from the aldo‐keto reductase (AKR1C) family, using HepG2 cell (human hepatoma cells) and MCF‐7 cell (human breast cancer cells). Estradiol increased mRNA levels of AKR1C1, AKR1C2, and AKR1C3 and protein levels of total AKR1C in HepG2 cells. Estradiol selectively enhanced levels of AKR1C2 mRNA in MCF‐7 cells. Thus, changes in the major metabolites of tibolone might result from changes in AKR1C family expression by patient estrogen status.