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Research ArticleArticle

Metabolism and Excretion of a New Antipsychotic Drug, Ziprasidone, in Humans

Chandra Prakash, Amin Kamel, Judith Gummerus and Keith Wilner
Drug Metabolism and Disposition July 1997, 25 (7) 863-000;
Chandra Prakash
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Amin Kamel
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Judith Gummerus
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Keith Wilner
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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 theCmax 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.

Footnotes

  • Send reprint requests to:Dr. Chandra Prakash, Department of Drug Metabolism, Central Research Division, Pfizer, Inc., Groton, CT 06340.

  • This work was presented in part at the 4th International Society for the Study of Xenobiotics Meeting, Seattle, WA, 1995.

  • ↵2 S. Walinsky et al., unpublished work.

  • ↵3 S. Zorn et al., unpublished work.

  • Abbreviations used are::
    ZIP
    ziprasidone (5-[2-{4-(1,2-benzisothiazol-3-yl)piperazin-1-yl}ethyl]-6-chloro-1,3-dihydro-indol-2-one) hydrochloride hydrate
    5-HT
    5-hydroxytryptamine
    TICI3
    titanium (III) chloride
    radio-HPLC
    HPLC with on-line radioactivity detection
    ZIP-SO
    ziprasidone sulfoxide
    ZIP-SO2
    ziprasidone sulfone
    OX-AA
    (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid
    BITP
    3-(piperazine-1-yl)-1,2-benzisothiazole
    BITP-SO
    BITP sulfoxide
    BITP-SO2
    BITP-sulfone
    OX-P
    6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one
    dihydro-ZIP
    6-chloro-5-(2-{4-[imino-(2-mercapto-phenyl)methyl]-piperazin-1-yl}ethyl)-1,3-dihydro-indol-2-one
    S-methyl-dihydro-ZIP
    6-chloro-5-(2-{4-[imino-(2-methylsulfanyl-phenyl)methyl]piperazin-1-yl}ethyl)-1,3-dihydro-indol-2-one
    S-methyl-dihydro-ZIP-SO
    6-chloro5-(2-{4-[imino-(2-methyl-sulfanyl-phenyl)-methyl]-piperazin-1-yl]ethyl}-1,3-dihydro-indol-2-one-S-oxide
    AUC
    area under the serum concentration-time curves
    Cmax
    maximum concentration
    tmax
    time to maximum concentration
    β-RAM
    radioactivity monitor
    CID
    collision-induced dissociation
    CNL
    constant neutral loss
    MRM
    multiple reaction monitoring
    MTBSTFA
    N(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide
    5-OH-ZIP
    5-hydroxy-ziprasidone
    TIC
    total ion current
    RAD
    radioactivity detector
    dihydro-ZIP-O2
    2-{4-[2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)-ethyl]-piperazine-1-carbonyl}-benzenesulfinic acid amide
    • Received December 12, 1996.
    • Accepted April 1, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 7
1 Jul 1997
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Research ArticleArticle

Metabolism and Excretion of a New Antipsychotic Drug, Ziprasidone, in Humans

Chandra Prakash, Amin Kamel, Judith Gummerus and Keith Wilner
Drug Metabolism and Disposition July 1, 1997, 25 (7) 863-000;

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Research ArticleArticle

Metabolism and Excretion of a New Antipsychotic Drug, Ziprasidone, in Humans

Chandra Prakash, Amin Kamel, Judith Gummerus and Keith Wilner
Drug Metabolism and Disposition July 1, 1997, 25 (7) 863-000;
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