17-ethinyl-7-alpha-methyl-19-nortestosterone and 3-hydroxytibolone

Tibolone has estrogenic effects on the vagina but not on the uterus. To explain this, levels of tibolone and estradiol and their metabolites were determined in serum, myometrium, and vagina. Thirty-four postmenopausal women with uterine prolapse received either no treatment, tibolone, E(2) or E(2) + medroxyprogesterone acetate (MPA) for 21 days, or a single dose of tibolone. Twenty +/- 6 hours after administration, >98% of the 3-hydroxytibolone metabolites in serum and tissues were disulfated. Of the unconjugated metabolites, the estrogenic 3alpha-hydroxytibolone predominated in serum, whereas the progestagenic/ androgenic Delta(4)-tibolone predominated in myometrium and vagina. Levels of disulfated metabolites in serum and tissues were higher (3- to 5-fold) after multiple dosing than after a single dose. Tissue:serum ratios were <1, except for Delta(4)-tibolone. In all groups, E(2) tissue levels were higher than serum levels; the percentage of serum E(1)S was >90%. Tibolone did not affect endogenous E(1), E(2), or E(1)S levels in serum, but in myometrium and vagina, E(1) levels were significantly higher and E(1)S levels tended to be lower than in controls. Serum and tissue levels of endogenous and exogenous E(1), E(2), and E(1)S were markedly increased 20 hours after E(2) or E(2) + MPA; the percentage of E(1)S and tissue:serum ratios were not affected. MPA had no effect on the degree of sulfation of E(1). Compared with serum, tissue levels of E(2) were high in all groups; absolute E(2) levels in control and tibolone groups were much lower than in the E(2) groups. Tibolone metabolite patterns are different in serum, myometrium, and vagina.

Topics: Aged; Estradiol; Estrone; Female; Humans; Medroxyprogesterone Acetate; Middle Aged; Myometrium; Norpregnenes; Postmenopause; Selective Estrogen Receptor Modulators; Tissue Distribution; Uterine Prolapse; Vagina

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.

Topics: Administration, Oral; Animals; Bile; Biotransformation; Chromatography, High Pressure Liquid; Drug Administration Schedule; Feces; Female; Gas Chromatography-Mass Spectrometry; Macaca fascicularis; Norpregnenes; Ovariectomy; Reproducibility of Results; Selective Estrogen Receptor Modulators; Sulfates; Tandem Mass Spectrometry

Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta(4)-tibolone), monosulfated (3alpha-sulfate,17beta-hydroxytibolone and 3beta-sulfate,17beta-hydroxytibolone), and disulfated (3alpha,17beta-disulfated-tibolone and 3beta,17betaS-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3alpha-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). Delta(4)-Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.

Topics: Administration, Oral; Animals; Biotransformation; Brain; Breast; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; Gas Chromatography-Mass Spectrometry; Macaca fascicularis; Molecular Structure; Norpregnenes; Ovariectomy; Reproducibility of Results; Selective Estrogen Receptor Modulators; Sulfates; Tandem Mass Spectrometry; Tissue Distribution; Uterus; Vagina