Received for publication December 4, 2006.
Revised April 5, 2007.
Accepted for publication April 5, 2007.

Selective tissue distribution of tibolone metabolites in mature ovariectomized female cynomolgus monkeys after multiple doses of tibolone

Abstract

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 hours after the final dose. The plasma and tissue levels of active, non-sulfated (tibolone, 3-hydroxytibolone, 3-hydroxytibolone, ⁴-tibolone), mono-sulfated (3-sulfate,17-hydroxytibolone, 3-sulfate,17-hydroxytibolone) and di-sulfated (3,17-di-sulfated-tibolone, 3,17S-di-sulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1-0.5 ng/mL (plasma) and 0.5-2 ng/g (tissues). In brain tissues, estrogenic 3-hydroxytibolone was predominant with 3-8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major non-sulfated metabolites were 3-hydroxytibolone and the androgenic/progestagenic ⁴-tibolone; di-sulfated metabolites were predominant. Remarkably high levels of mono-sulfated metabolites were found in the proximal vagina. In endometrium, myometrium and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites high (about 98% di-sulfated). ⁴-tibolone/3-hydroxytibolone ratios were 2-3 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.

Key words: blood-brain barrier, distribution, drug development, drug distribution, enzyme mechanism, female reproductive system toxicology, metabolite kinetics, steroids, sulfate conjugation, sulfotransferases

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