Isolation and identification of major metabolites of tixocortol pivalate in human urine.

The metabolism of tixocortol pivalate (PIVALONE), an anti-inflammatory steroid without systemic glucocorticoid effects, has been investigated in man. The analysis was conducted using urine samples collected from two volunteers who had received a 2-g oral dose of 14C-tixocortol pivalate as an oral suspension. Metabolites were purified and isolated from urine by normal phase HPLC, and structural identification was achieved by desorption chemical ionization/NH3 and electron impact/direct line introduction mass spectrometry. Unchanged tixocortol pivalate was not detected in urine; all metabolites were sulfo- and glucurono-conjugates. Metabolites were identified in the neutral steroid fraction obtained after hydrolysis of conjugates. Metabolic transformations in common with cortisol were reduction of the 3-keto, delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol, and cleavage of the side chain at C-17. Specific metabolic pathways involving the C-21 thiol ester function were transformations into methylthio, methylsulfinyl and methylsulfonyl derivatives, and a reductive cleavage of the C-21-S bond leading to 21-methyl structures. Since none of these metabolites had binding affinity for glucocorticoid receptors in vitro, fast and extensive transformation of tixocortol pivalate into inactive metabolites provides an explanation for the large dissociation between the topical and systemic activities of this drug.