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Department of Drug Metabolism, Central Research Division,
Pfizer, Inc.
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.
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