Metabolism of the antipsychotic drug tiospirone in humans

Metabolism of the antipsychotic drug tiospirone was studied in humans after a single 60-mg oral dose of [14C]tiospirone. Metabolites were isolated from a 0-24 hr pooled urine from eight subjects, which represented 39% of the dose, and purified to homogeneity by HPLC. Purified metabolites were identified by desorption chemical ionization mass spectrometry in the positive ion mode with methane as a reagent gas. Structures of the metabolites were confirmed by coelution on HPLC in several systems with synthetic standards. In addition to unchanged tiospirone, five metabolites of tiospirone were identified and one additional metabolite was partially identified. Based on the structures of these metabolites, five routes of metabolism of tiospirone were identified: N-dealkylation of the butyl side chain attached to the piperazinyl nitrogen, hydroxylation alpha to the glutarimidyl carbonyl at the 6'-position on the spiro ring, hydroxylation at the 3'-position on the spiro ring, oxidation at sulfur resulting in the formation of sulfones, and oxidation at carbon alpha to the piperazinyl nitrogen resulting in the formation of a lactam-sulfone. The major urinary metabolites were benzisothiazole piperazine sulfone and its lactam derivative, accounting for 5.0 and 4.3% of the dose, respectively. The identified metabolites accounted for 50% of the total radioactivity in the urine (approximately 20% of the dose). The remaining radioactive components were extremely heterogeneous and could not be isolated in sufficient quantities to characterize. A scheme for the metabolism of tiospirone in humans is proposed.