The in Vivo Human Metabolism of Tibolone

Abstract

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...

Tibolone Metabolism in Human Liver Is Catalyzed by 3α/3β-Hydroxysteroid Dehydrogenase Activities of the Four Isoforms of the Aldo-Keto Reductase (AKR)1C Subfamily

“…The conversion of tibolone to 3␤-hydroxytibolone was quantitative, and no conjugation was detected. HepG2 cells have high glucuronyltransferase activity but low sulfotransferase activity (Song et al, 1998;Narasaka et al, 2000;Duanmu et al, 2002), and this supports the observation that the 3-hydroxymetabolites of tibolone are not glucuronidated (Sandker et al, 1994;Vos et al, 2002). No formation of 3␣-hydroxytibolone was observed, consistent with the lack of AKR1C4 expression in HepG2 cells.…”

“…8D). Tibolone and its 3-hydroxymetabolites are efficiently converted into sulfate conjugates via sulfotransferases (Vos et al, 2002). Human hydroxysteroid sulfotransferase SULT2A1 and human estrogen sulfotransferase SULT2E1 (and to a minor extent human cholesterol sulfotransferase SULT2B1b) catalyze this reaction in vitro (Falany et al, 2004) and are expressed in human hepatocytes (Song et al, 1998;Narasaka et al, 2000;Duanmu et al, 2002).…”

“…1). The major active circulating metabolite is the 3␣-hydroxyderivative (Timmer et al, 2002;Vos et al, 2002), and over 75% tibolone and its metabolites are found to be in the inactive sulfated form. Of a total administered oral dose, 50% is found in the feces as 3␣-hydroxyand 17␤-hydroxy-sulfates, suggesting that transformation by intestinal mucosa and bacteria may contribute to the metabolic profile (Vos et al, 2002).…”

“…1). The major active circulating metabolite is the 3␣-hydroxyderivative (Timmer et al, 2002;Vos et al, 2002), and over 75% tibolone and its metabolites are …”

Histomorfometria do tecido ósseo em ratas castradas tratadas com tibolona

“…Os esteroides sexuais têm papel primordial na manutenção da homeostasia óssea, prevenindo e tratando a osteoporose (4,11,41) . Nas várias opções terapêuticas para a pós-menopausa, a tibolona, um esteroide sintético 19-nor derivado do noretinodrel, estruturalmente diferente do estradiol e dos moduladores seletivos dos receptores de estrogênio (SERMs), é considerada uma opção de grande valor, sendo um composto de ação tecidual específica com efeitos favoráveis em diversos órgãos, sem estimulação dos tecidos mamário e endometrial (22,27,39,42,45) . Possui ação especifica para os tecidos, distinguindo-se das terapêuticas hormonais de substituição (THS) convencionais.…”