This paper is available online at http://dmd.aspetjournals.org ABSTRACT:In vivo metabolism of tibolone was studied in three healthy postmenopausal volunteers after daily oral administration of 2.5 mg of tibolone for 5 days and a single dose of 2.5 mg Х 555 kBq of Tibolone [(7␣,17␣)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] is a tissue-specific compound with favorable effects on bone, vagina, climacteric symptoms, mood, and sexual well being in postmenopausal women. It has not been observed to stimulate the endometrium (Moore, 1999) or the breast, as demonstrated by the lower incidence of breast tenderness and lower mammographic density (Valdivia and Ortega, 2000). Therefore, in some tissues, tibolone has different effects than estrogens.The metabolism of tibolone has been studied in female rats, rabbits, and dogs. A considerable number of metabolites were identified in this study using 1 H NMR and mass spectroscopy, and qualitative and quantitative differences between species were observed (Jacobs et al., 1992;Verhoeven et al., 2002). Major phase I metabolic routes were the reduction of 3-keto to 3␣-or 3␤-hydroxy moieties, and the major phase II metabolic route was sulfate conjugation of the hydroxy groups at C3 and C17. Profiling of the target organs showed a tissue-specific distribution of metabolites. The majority of these metabolites existed as sulfate conjugates. These data in animals indicate that tibolone exerts its tissue-specific activities, at least partly, due to its tissue-specific metabolism and distribution. In addition, the presence of local sulfatases may convert inactive sulfated metabolites to active forms.The linearity of the pharmacokinetic profile of tibolone was studied in three groups of nine healthy female volunteers using 1.25, 2.5, and 5 mg of tibolone, respectively. The pharmacokinetic profile was mainly based on the primary phase I plasma metabolites (i.e., tibolone, 3␣-hydroxy tibolone, 3␤-hydroxy tibolone, and ⌬ 4 -tibolone). The steady state was attained by day 5 in all three dose groups. Since in most cases the plasma concentration of tibolone and ⌬ 4 -tibolone was below the detection limit, their elimination half-life could not reliably be determined. The geometric mean value of the elimination half-life of 3␣-hydroxy tibolone for the three dose levels ranged from 7.2 to 8.5 h. The very low plasma concentrations of the parent compound and the even lower concentrations of the ⌬ 4 -isomer, in combination with the considerably higher concentrations of the 3␣-and 3␤-hydroxy metabolites, indicated that tibolone is extensively metabolized, predominantly by hydroxylation at C3.Human biotransformation pathways need to be identified, and the possibility of metabolic or pharmacokinetic interactions occurring with coadministered compounds need to be addressed during the development of a drug. In vitro approaches are usually used to study these issues and to evaluate their potential clinical relevance. These in vitro studies generally focus on cytochrome P450, which is a collecti...