C. Prakash et al., CHARACTERIZATION OF THE NOVEL BENZISOTHIAZOLE RING-CLEAVED PRODUCTS OF THE ANTIPSYCHOTIC DRUG ZIPRASIDONE, Drug metabolism and disposition, 25(7), 1997, pp. 897-901
Characterization of two novel benzisothiazole ring cleaved metabolites
of the antipsychotic drug, ziprasidone (ZIP), in rat has been describ
ed. 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 base
d on tandem mass spectrometry in combination with chemical derivatizat
ion techniques. M6 and Mg were unaffected upon treatment with rt-butyl
dimethylsilyl)-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 meta
bolites were owing to N-oxidation and/or aromatic hydroxylation. M6 an
d M9 were generated only when in vitro incubations of ZIP were conduct
ed with human liver S-9 fraction in the presence of S-adenosyl-L-methi
onine. 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 Mg was unambiguously confirmed by comparing the LC/MS
retention time and mass spectral data with synthetic standard. A mech
anism for the formation of these metabolites from ZIP is proposed.