Abstract

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 theC_max 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 asS-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 orN-dearylation of the benzisothiazole moiety. The identified metabolites accounted for >90% of total radioactivity recovered in urine.