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Departments of
Drug Metabolism (C.P., A.K.) and
Clinical
Research (J.G., K.W.), Central Research Division, Pfizer, Inc.
The pharmacokinetics, metabolism, and excretion of a new
antipsychotic drug, ziprasidone, were studied in four normal male volunteers after oral administration of a single 20 mg dose of a
mixture of 14C- and 3H-labeled ziprasidone.
Blood, urine, and feces were collected at various intervals for
determination of total radioactivity and metabolic profiles. Eleven
days after the dose, 20.3 ± 1% of the administered radioactivity
was recovered in the urine and 66.3 ± 4.8% in feces. The
absorption of ziprasidone was rapid, and the
Cmax for ziprasidone and metabolites occurred
at 2 to 6 hr postdose. Mean peak serum concentration of unchanged drug was 45 ng/ml and a mean AUC(0-t) of 335.7 ng
· hr/ml. Mean peak serum concentration of total radioactivity
(average of 3H and 14C) was 91 ng-eq/ml and a
mean AUC(0-t) of 724.6 ng-eq · hr/ml. On the
basis of AUC(0-t) values, ~46% of
circulating radioactivity was attributable to unchanged drug.
Ziprasidone was extensively metabolized and only a small amount (<5%
of the administered dose) was excreted in urine and feces as unchanged
drug. Twelve metabolites in human urine and serum were identified by
ion-spray LC/MS and LC/MS/MS with simultaneous monitoring of
radioactivity. The major urinary metabolites were identified as
oxindole-acetic acid and its glucuronide conjugate, benzisothiazole-3-yl-piperazine (BITP), BITP-sulfoxide,
BITP-sulfone and its lactam, ziprasidone-sulfoxide, and sulfone
similar to those identified in rats. In addition, two novel metabolic
pathways (reductive cleavage and N-dearylation of the
benzisothiazole ring) were identified for ziprasidone in humans.
The metabolites resulted by these pathways were characterized as
S-methyl-dihydroziprasidone, S-methyl-dihydro-ziprasidone sulfoxide, and
6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one, respectively. Ziprasidone sulfoxide and sulfone were the major metabolites in human serum. The affinities of the sulfoxide and sulfone
metabolites for 5-HT2 and D2 receptors are low
with respect to ziprasidone, and are thus unlikely to contribute to its
antipsychotic effects. Structures of the major metabolites were
confirmed by chromatographic and spectroscopic comparisons to synthetic
standards. Based on the structures of these metabolites, four routes of
metabolism of ziprasidone were identified: 1)
N-dealkylation of the ethyl side chain attached to the
piperazinyl nitrogen, 2) oxidation at sulfur resulting in
the formation of sulfoxide and sulfone, 3) reductive
cleavage of the benzisothiazole moiety, and 4)
hydration of the C=N bond and subsequent sulfer oxidation or
N-dearylation of the benzisothiazole moiety. The identified
metabolites accounted for >90% of total radioactivity recovered in
urine.
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