The in Vivo Human Metabolism of Tibolone

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 ≅ 555 kBq of [¹⁴C]tibolone on day 6. The 0- to 192-h recovery of radioactivity in urine and feces was 31.2 ± 10.5 and 53.7 ± 5.1%, respectively. Total 0- to 192-h recovery ranged from 78.5 to 94.2% of the dose and averaged 84.9%. Metabolites were putatively identified using high-pressure liquid chromatography in plasma, urine, and feces. The most important phase I metabolic reactions were reduction of the 3-keto group to 3α- and 3β-hydroxy metabolites, a shift of the Δ⁵⁽¹⁰⁾-double bond to a Δ⁴⁽⁵⁾-double bond, a reduction of the Δ⁴⁽⁵⁾-double bond to 5α,10-dihydro or 5β,10-dihydro metabolites, and hydroxylation at C2 and C7. The most important phase II metabolic reaction is sulfation of the C17 hydroxy group of tibolone and sulfation of the C3 hydroxy groups. In the circulation, over 75% of tibolone and its metabolites are present in the sulfated form. Local metabolism and local sulfatases may contribute to the tissue-specific activity. Using human microsomes, tibolone, 3α-hydroxy tibolone, 3β-hydroxy tibolone, and Δ⁴-tibolone appeared to be at least 50-fold less potent inhibitors of CYP1A2, CYP2C9, CYP2E1, and CYP3A4 compared with enzyme-selective inhibitors. Tibolone and its metabolites, therefore, are not likely to play a clinically significant role at the level of these cytochrome P450 enzymes with regard to the metabolism of coadministered drugs.