著者

熊谷 雄治 藤田 朋恵 横田 愼一 澤田 実花 井澤 志名野 鈴木 勇一 立岡 和弘 庄田 隆 矢後 和夫

出版者

The Japanese Society of Clinical Pharmacology and Therapeutics

雑誌

臨床薬理 (ISSN:03881601)

巻号頁・発行日

vol.33, no.5, pp.205-213, 2002-09-30 (Released:2010-06-28)

参考文献数

8

---

Objectives: Tibolone (KB-889) is a novel compound that possesses tissue-specific hormonal effects. We investigated the pharmacokinetics of tibolone in postmenopausal women in four pharmacokinetic studies, namely a dose linearity study, a multiple dose study, a study in fasted condition, and a study in elderly. In this report, the results obtained from the above four studies are summarized.Methods: In the dose linearity study, a single dose of 0.5 mg, 1 mg and 2 mg of tibolone was administered to 6 postmenopausal women using a 3-period crossover method with at least a 7-day wash-out period between treatments. In the multiple dose study, 2 mg of tibolone was administered once daily for 4 days to 6 postmenopausal women. In the study in fasted condition, a single dose of 2 mg of tibolone was administered to 6 postmenopausal women after overnight fasts. In the study in elderly, a single dose of 2 mg of tibolone was administered to 6 elderly women aged 65 or older. Plasma and urine concentrations of tibolone and its metabolites were measured.Results and Conclusion: Plasma concentrations of the 3α-OH and 3β-OH metabolites of tibolone were measured, since the levels of tibolone and its Δ4-isomer were under or near the detection limits. After single dose administration of 0.5, 1 and 2 mg of tibolone, the means of Cmax and AUC0-12h of plasma 3α-OH metabolite were 2.3, 3.5 and 6.5 ng/mL and 10.2, 18.5 and 36.7 ng·Eh/mL, respectively, and those of 3β-OH metabolites were 0.9, 1.7 and 3.1 ng/mL and 4.6, 8.8 and 17.7 ng·Eh/mL, respectively. The means of Tmax and T1/2 (6-12h) of plasma 3α-OH and 3β-OH metabolites were between 3.7 and 5.7 h, and between 3.2 and 4.4 h, respectively. The pharmacokinetic properties of tibolone were considered to be linear within the dose range of 0.5 mg to 2 mg. In the multiple dose study, no accumulation was found. When comparing the pharmacokinetic parameters obtained from the study in fasted condition with those of day 1 of the multiple dose study, the absorption of tibolone was rapid under fasted condition, but AUC was not influenced by food intake. [The means of Tmax of 3α-OH and 3β-OH metabolites were 1.17 and 1.33 h in fasted condition, and 3.83 and 4.00 h on day 1 of multiple dose.] Finally no difference in pharmacokinetics was found between postmenopausal women and elderly women in the comparison of the pharmacokinetic parameters obtained from the study in the elderly and those of day 1 of the multiple dose study.