The in vivo metabolism of tibolone in animal species

Abstract

The in vivo tissue distribution and metabolism of tibolone was studied in different animals to further investigate the compound's tissue-specificity. Tibolone's metabolism was studied in vivo in rats and rabbits by administration of [16-3H]-tibolone and the metabolic pattern was determined in urine and faeces after oral administration to female rats and dogs. The main excretory pathway was found to be excretion in the faeces. Important phase-I metabolic routes were the reduction of the 3-keto to the 3a- or 3beta-hydroxy functions with a preference for 3alpha-OH in rats and for 3beta-OH in dogs. To a lesser extent, hydroxylation reactions at C2 and C7, and a shift of the delta5(10)-double bond to a delta4(5)-position also occurred. The main phase-II metabolic route was sulphate conjugation of the hydroxyl groups at C3 and C17. Since the oxidation reactions form only a minor part of the metabolism of tibolone, it is concluded that the cytochrome P450 enzymes do not play an important role in tibolone's metabolism. For both phases, quantitative differences were found between the species. In human similar metabolites are found. Profiling of the target organs in female rats and rabbits showed a tissue-specific distribution of metabolites. The majority of the metabolites existed as sulphate conjugates and no glucuronidated conjugates were observed. The same metabolites were found in both the circulation and the tissues. However, different tissues had quantitatively different metabolic profiles.

The in Vivo Human Metabolism of Tibolone

“…The in vivo human results presented in this article confirm the metabolic routes previously shown in in vitro studies (Sandker et al, 1994) and in vivo in rat, rabbit, and dog (Verhoeven et al, 2002). The most important phase I metabolic reaction found for tibolone in postmenopausal women is the reduction of the 3-keto group to 3␣-and 3␤-hydroxy metabolites, a reaction catalyzed by 3␣-hydroxysteroid-dehydrogenase/isomerase (HSD) and 3␤-HSD, respectively.…”

“…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.…”

“…• 3␣,17␤-Disulfate tibolone, 3␣-hydroxy-17␤-sulfate tibolone, 3␣-sulfate tibolone, isolated from animal studies and identified by mass spectometry and NMR (Jacobs et al, 1992;Verhoeven et al, 2002), and Org OD14, Org OM38, Org 4094, and Org 30126 were used as reference compounds for profiling purposes.…”

Stereoselectivity in metabolic 3-reduction of tibolone in healthy Chinese female volunteers

“…Differences in the 3α/β-hydroxylization metabolism of tibolone, as well as desogestrel, by different species of animals have been confirmed by Verhoeven et al [11,12] : both drugs had mainly 3α-hydroxyl metabolites in rats, but 3β-hydroxyl metabolites in dogs. Because 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroids dehydrogenase reduce 3-keto steroids, polymorphism for 3α/β-hydroxylization metabolism can be explained by individual differences in 3α-hydroxysteroid dehydrogenase activity and 3β-hydroxysteroid dehydrogenase activity.…”

Metabolism of tibolone and its metabolites in uterine and vaginal tissue of rat and human origin

“…Alternatively, the conversion may go via tibolone as an intermediate. Indeed it has been shown in rats and dogs that the 3␣ or 3␤ deutered OH group is removed during epimerisation [19].…”