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

Pharmacokinetic parameters of tibolone and metabolites in plasma, urine, feces and bile from ovariectomized cynomolgus monkeys after a single dose or multiple doses of tibolone

Abstract

Levels of non-sulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from 6 ovariectomized, mature female cynomolgus monkeys after a single dose and multiple oral doses (including bile) of tibolone using validated GC-MS and LC-MS/MS assays. In plasma, the predominant non-sulfated metabolite after single and multiple dosing was the estrogenic 3-hydroxytibolone; levels of the estrogenic 3-hydroxytibolone were 10-fold and of progestagenic/androgenic ⁴-tibolone 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3S,17S-tibolone; levels of 3S,17S-tibolone were about 2-fold and mono-sulfated 3-hydroxymetabolites about 10-fold lower. After multiple doses, AUCs of non-sulfated metabolites were lower (2-fold), and of sulfated metabolites 25% higher. In plasma, > 95% metabolites were di-sulfated. In urine, levels of all metabolites after single and multiple doses were low. After a single dose, high levels of 3-hydroxytibolone and the 3-mono-sulfated metabolites [3S,17OH-tibolone and 3S,17OH-tibolone] were found in feces. After multiple dosing, 3-hydroxytibolone increased and the ratio of 3/3-hydroxytibolone became about 1. The predominant sulfated metabolite was 3S,17S-tibolone. Levels of all metabolites in feces were higher after multiple than after a single dose. Levels of non-sulfated and 3-mono-sulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except mono-sulfates. This may contribute to the metabolite content of the feces after multiple doses. 3-Hydroxytibolone and 3S,17S-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. Feces was the major excretion route.

Key words: biliary excretion, drug distribution, excretion, half-life, pharmacokinetics, renal elimination, steroids, sulfate conjugation, sulfotransferases

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