METABOLISM AND EXCRETION OF THE NOVEL ANTIPSYCHOTIC DRUG ZIPRASIDONE IN RATS AFTER ORAL-ADMINISTRATION OF A MIXTURE OF C-14-LABELED AND H-3-LABELED ZIPRASIDONE

The metabolism and excretion of ziprasidone (5-[2-[4-(1,2-benzisothiaz ol-3-yl)piperazin-1 -yl]ethyl]-6-chloroindolin-2-one hydrochloride hyd rate) were studied in Long Evans rats after oral administration of a s ingle dose of a mixture of C-14- and H-3-labeled ziprasidone. The radi oactive 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 excre tion in urine and bile suggested that at least 41% of the drug was abs orbed, Absorption of ziprasidone was rapid, and the mean plasma concen trations 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% o f the circulating radioactivity (average of C-14 and H-3) was attribut able to metabolites in male and female rats, respectively. Ziprasidone was extensively metabolized in rats, and only a small amount of zipra sidone was excreted as unchanged drug, Twelve metabolites were identif ied by ion spray LC/MS, using a combination of parent ion and product ion scanning techniques. The structures of eight metabolites were unam biguously confirmed by coelution, on HPLC with synthetic standards, an d four additional metabolites were partially identified, There was a g ender-related difference in the excretion of urinary metabolites in Lo ng Evans rats, The major route of metabolism in male rats involved N-d ealkylation. In female rats the major metabolites were due to oxidatio n at the benzisothiazole ring, Based on the structures of these metabo lites, four major and two minor routes of metabolism of ziprasidone we re identified. The major routes included 1) N-dealkylation of the ethy l side chain attached to the piperazinyl nitrogen, 2) oxidation at the sulfur, resulting in the formation of sulfoxide and sulfone, 3) oxida tion on the benzisothiazole moiety (other than sulfur), and 4) hydrati on of the C=N bond and subsequent oxidation at the sulfur of the benzi sothiazole moiety. The minor routes involved N-oxidation on the pipera zine ring and hydrolysis of the oxindole moiety.