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Pharmacokinetic Parameters of Tibolone and Metabolites in Plasma, Urine, Feces, and Bile from Ovariectomized Cynomolgus Monkeys after a Single Dose or Multiple Doses of Tibolone

NV Organon, Oss, The Netherlands

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 3-hydroxytibolone; levels of the estrogenic 3ß-hydroxytibolone were 10-fold lower and of progestagenic/androgenic ⁴-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3S,17ßS-tibolone; levels of 3ßS,17ßS-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 3ß-hydroxytibolone and the 3-monosulfated metabolites (3ßS,17ßOH-tibolone and 3S,17ßOH-tibolone) were found in feces. After multiple dosing, 3-hydroxytibolone increased, and the ratio of 3/3ß-hydroxytibolone became about 1. The predominant sulfated metabolite was 3S,17ßS-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. 3ß-Hydroxytibolone and 3S,17ßS-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.

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				H. A. M. Verheul, M. L. P. S. van Iersel, L. P. C. Delbressine, and H. J. Kloosterboer Selective Tissue Distribution of Tibolone Metabolites in Mature Ovariectomized Female Cynomolgus Monkeys after Multiple Doses of Tibolone Drug Metab. Dispos., July 1, 2007; 35(7): 1105 - 1111. [Abstract] [Full Text] [PDF]