0090-9556/97/2502-0206-0218$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 2

Metabolism and Excretion of the Novel Antipsychotic Drug Ziprasidone in Rats after Oral Administration of a Mixture of ¹⁴C- and ³H-Labeled Ziprasidone

Chandra Prakash, Amin Kamel, Wayne Anderson, and Harry Howard

Departments of Drug Metabolism (C.P., A.K., W.A.) and Medicinal Chemistry (H.H.), Central Research Division, Pfizer Inc.

The metabolism and excretion of ziprasidone (5-[2-{4-(1,2-benzisothiazol-3-yl)piperazin-1-yl}ethyl]-6-chloroindolin-2-one hydrochloride hydrate) were studied in Long Evans rats after oral administration of a single dose of a mixture of ¹⁴C- and ³H-labeled ziprasidone. The radioactive dose was quantitatively recovered over 7 days in both male and female rats. The percentage of the dose excreted in urine, bile, and feces of rats was 21.6, 19.2, and 55.6%, respectively. The total excretion in urine and bile suggested that at least 41% of the drug was absorbed. Absorption of ziprasidone was rapid, and the mean plasma concentrations of the unchanged drug and metabolites were slightly higher in the female rats than in the males. The maximal plasma concentrations for ziprasidone and metabolites were reached at 1 hr in both male and female rats. Based on AUC (0-12 hr) values, approximately 59 and 52% of the circulating radioactivity (average of ¹⁴C and ³H) was attributable to metabolites in male and female rats, respectively. Ziprasidone was extensively metabolized in rats, and only a small amount of ziprasidone was excreted as unchanged drug. Twelve metabolites were identified by ion spray LC/MS, using a combination of parent ion and product ion scanning techniques. The structures of eight metabolites were unambiguously confirmed by coelution on HPLC with synthetic standards, and four additional metabolites were partially identified. There was a gender-related difference in the excretion of urinary metabolites in Long Evans rats. The major route of metabolism in male rats involved N-dealkylation. In female rats the major metabolites were due to oxidation at the benzisothiazole ring. Based on the structures of these metabolites, four major and two minor routes of metabolism of ziprasidone were identified. The major routes included 1) N-dealkylation of the ethyl side chain attached to the piperazinyl nitrogen, 2) oxidation at the sulfur, resulting in the formation of sulfoxide and sulfone, 3) oxidation on the benzisothiazole moiety (other than sulfur), and 4) hydration of the CN bond and subsequent oxidation at the sulfur of the benzisothiazole moiety. The minor routes involved N-oxidation on the piperazine ring and hydrolysis of the oxindole moiety.