TY - JOUR T1 - Selective Tissue Distribution of Tibolone Metabolites in Mature Ovariectomized Female Cynomolgus Monkeys after Multiple Doses of Tibolone JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1105 LP - 1111 DO - 10.1124/dmd.106.014118 VL - 35 IS - 7 AU - H. A. M. Verheul AU - M. L. P. S. van Iersel AU - L. P. C. Delbressine AU - H. J. Kloosterboer Y1 - 2007/07/01 UR - http://dmd.aspetjournals.org/content/35/7/1105.abstract N2 - 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, 3α-hydroxytibolone, 3β-hydroxytibolone, and Δ4-tibolone), monosulfated (3α-sulfate,17β-hydroxytibolone and 3β-sulfate,17β-hydroxytibolone), and disulfated (3α,17β-disulfated-tibolone and 3β,17βS-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 3α-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 3α-hydroxytibolone and the androgenic/progestagenic Δ4-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). Δ4-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. The American Society for Pharmacology and Experimental Therapeutics ER -