METABOLISM AND EXCRETION OF A NEW ANTIPSYCHOTIC DRUG, ZIPRASIDONE, INHUMANS

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 C-14- and H -3-labeled ziprasidone. Blood, urine, and feces were collected at vari ous intervals for determination of total radioactivity and metabolic p rofiles. Eleven days after the dose, 20.3 +/- 1% of the administered r adioactivity was recovered in the urine and 66.3 +/- 4.8% in feces. Th e absorption of ziprasidone was rapid, and the C-max for ziprasidone a nd metabolites occurred at 2 to 6 hr postdose. Mean peak serum concent ration of unchanged drug was 45 ng/ml and a mean AUC((o-t)) of 335.7 n g . hr/ml. Mean peak serum concentration of total radioactivity (avera ge of H-3 and C-14) was 91 ng-eq/ml and a mean AUC((o-t)) of 724.6 ng- eq . hr/ml. On the basis of AUC((o-t)) values, similar to 46% of circu lating radioactivity was attributable to unchanged drug. Ziprasidone w as extensively metabolized and only a small amount (<5% of the adminis tered dose) was excreted in urine and feces as unchanged drug. Twelve metabolites in human urine and serum were identified by ion-spray LC/M S and LC/MS/MS with simultaneous monitoring of radioactivity. The majo r urinary metabolites were identified as oxindole-acetic acid and its glucuronide conjugate, benzisothiazole-3-yl-piperazine (BITP), BITP-su lfoxide, BITP-sulfone and its lactam, ziprasidone-sulfoxide, and sulfo ne similar to those identified in rats. In addition, two novel metabol ic pathways (reductive cleavage and N-dearylation of the benzisothiazo le ring) were identified for ziprasidone in humans. The metabolites re sulted by these pathways were characterized as S-methyl-dihydroziprasi done, S-methyl-dihydro-ziprasidone sulfoxide, and 6-chloro-5-(2-pipera zin-1- yl-ethyl)-1,3-dihydro-indol-2-one, respectively. Ziprasidone su lfoxide and sulfone were the major metabolites in human serum. The aff inities of the sulfoxide and sulfone metabolites for 5-HT2 and D-2 rec eptors are low with respect to ziprasidone, and are thus unlikely to c ontribute to its antipsychotic effects. Structures of the major metabo lites 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-dealkyl ation of the ethyl side chain attached to the piperazinyl nitrogen, 2) oxidation at sulfur resulting in the formation of sulfoxide and sulfo ne, 3) reductive cleavage of the benzisothiazole moiety, and 4) hydrat ion of the C=N bond and subsequent sulfer oxidation or N-dearylation o f the benzisothiazole moiety. The identified metabolites accounted for >90% of total radioactivity recovered in urine.