Pharmacokinetics of tibolone in early and late postmenopausal women

Abstract

Aims Tibolone is a tissue-specific compound with favourable effects on bone, vagina, climacteric symptoms, mood and sexual well being in postmenopausal women, without stimulating the endometrium or breast. Since tibolone is used for the treatment of both young and elderly postmenopausal women, its pharmacokinetics were studied to investigate potential differences with age. In addition, the bioequivalence of the 1.25 and 2.5 mg tablets was evaluated. Methods Single doses of 1.25 or 2.5 mg of tibolone were given in a double-blind, randomized, two-way cross-over study to women aged between 45 and 55 years or between 65 and 75 years of age. Results Age did not have a significant effect on C max , t max , and t 1/2 of tibolone and its metabolites and on the body weight standardized oral clearance (CL/F kg x1 ) of the 3a-and 3b-hydroxy tibolones. In early postmenopausal women, significantly lower values were found for the AUC(0,16 h), and AUC(0,?) of 3a-hydroxy tibolone 24.6t6.6 vs 29.2t4.9 and 27.1t6.9 vs 32.3t6.5 ng ml x1 h for the 1.25 mg tablet, respectively, and 45.4t13.9 vs 55.7t14.1 and 49.6t14.6 vs 62.6t17.3 ng ml x1 h for the 2.5 mg tablet, respectively. When these values were adjusted for the significantly higher body weight of the early postmenopausal women, the differences disappeared. No significant differences between early and late postmenopausal women were found for the AUC(0,8 h), and AUC(0,?) of 3b-hydroxy tibolone. The rate of absorption of tibolone and the rates of absorption or formation of the 3a-and 3b-hydroxy tibolones were significantly higher after the 1.25 mg dose than after the 2.5 mg tablet, resulting in increases of 32%, 27% and 17% for the dose normalized-C max of tibolone and the 3a-and 3b-hydroxy tibolones, respectively. t max for tibolone and its metabolites was 12-27% less after 1.25 mg compared to 2.5 mg, which was statistically significant. The two formulations were bioequivalent with respect to the dose-normalized AUC(0,?) and the AUC (0, Conclusions The pharmacokinetics of tibolone are similar in early (age 45-55 years) and late (65-75 years) postmenopausal women. The 2.5 and 1.25 mg tablets are bioequivalent with respect to the extent of absorption. The rate of absorption or formation of the metabolites of tibolone were not bioequivalent, but these differences are considered to have no clinical relevance in view of the chronic administration of tibolone.

Tibolone Is Metabolized by the 3α/3β-Hydroxysteroid Dehydrogenase Activities of the Four Human Isozymes of the Aldo-Keto Reductase 1C Subfamily: Inversion of Stereospecificity with a Δ5(10)-3-Ketosteroid

“…However, AKR1C4 is exclusively expressed in the liver and predominantly catalyzes the formation of 3␣-hydroxytibolone. Therefore, these data may account for the fact that 3␤-hydroxytibolone is the major metabolite in tibolone target tissues and 3␣-hydroxytibolone is the major metabolite in the circulation (Blom, 2001;Timmer et al, 2002;Vos et al, 2002).…”

“…These reactions occur in the liver and intestine as well as in tibolone target tissues and are essential for 1) the apparent tissue-specific actions of tibolone (Kloosterboer and Ederveen, 2003) and 2) the catabolic clearance of the drug (Timmer et al, 2002;Vos et al, 2002). We previously demonstrated that the four human AKR1C isoforms catalyze the reduction of 5␣-DHT into 3␣-and 3␤-androstanediol (Steckelbroeck et al, 2004).…”

“…The plasma half-life of the two hydroxymetabolites is 7 h (Timmer et al, 2002), and the major phase I metabolite in the circulation is 3␣-hydroxytibolone (Vos et al, 2002). Reduction of the 3-keto-moiety of tibolone is a prerequisite for the formation of sulfate conjugates at the C3 and C17 hydroxy groups (Vos et al, 2002) via phase II sulfotransferases.…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…The alcohols are more potent than parent at the estrogen receptor, while the alkene isomer is more potent at the androgen receptor (Escande et al, 2009). The 3a-hydroxy isomer is present at more than 9-fold greater concentrations than tibolone (Timmer et al, 2002) and thus can be estimated to have a 20-fold greater contribution than tibolone itself, assuming other distributional aspects are similar between parent and metabolite. The 3b isomer is also present at greater concentrations, but not as much as the other isomer.…”

Stereoselectivity in metabolic 3-reduction of tibolone in healthy Chinese female volunteers

“…The pharmacokinetics of tibolone in female patients have been studied recently, and the plasma concentrations of 3α-HMN and 3β-HMN were determined by using a gas chromatography-mass spectrometry (GC-MS) method [9] . However, the pharmacokinetics of tibolone metabolism in a Chinese human population have not been studied.…”