Characterization of the novel benzisothiazole ring-cleaved products of the antipsychotic drug ziprasidone.

Characterization of two novel benzisothiazole ring cleaved metabolites of the antipsychotic drug, ziprasidone (ZIP), in rat has been described. Metabolites designated M6 and M9 were isolated from urine and bile of the rat dosed with radiolabeled ZIP and purified by reversed phase HPLC. The chemical structures of these metabolites were assigned based on tandem mass spectrometry in combination with chemical derivatization techniques. M6 and M9 were unaffected upon treatment with N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide. Reaction of M9 with aqueous TiCl3 also did not change the HPLC retention time or the CID spectrum of metabolite M9. These data excluded the possibility that these metabolites were owing to N-oxidation and/or aromatic hydroxylation. M6 and M9 were generated only when in vitro incubations of ZIP were conducted with human liver S-9 fraction in the presence of S-adenosyl-L-methionine. Based on these data, metabolites M6 and M9 were identified as S-methyl-dihydro-ZIP and S-methyl-dihylro-ZIP-sulfoxide, respectively. The structure of M9 was unambiguously confirmed by comparing the LC/MS retention time and mass spectral data with synthetic standard. A mechanism for the formation of these metabolites from ZIP is proposed.