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First published on April 8, 2005; DOI: 10.1124/dmd.105.004036

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Received for publication March 1, 2005.
Revised April 6, 2005.
Accepted for publication April 6, 2005.

CHARACTERIZATION OF A NOVEL METABOLITE INTERMEDIATE OF ZIPRASIDONE IN HEPATIC CYTOSOLIC FRACTIONS OF RAT, DOG AND HUMAN BY ESI-MS/MS, H/D EXCHANGE AND CHEMICAL DERIVATIZATION

Zhuang Miao 1, Kamel Amin 1, Chandra Prakash 2*

1 Pfizer 2 Pfizer Global Research & Development

* Address correspondence to: E-mail: chandra_prakash{at}groton.pfizer.com

Abstract

Ziprasidone (geodone), a novel atypical antipsychotic agent, is recently approved for the treatment of schizophrenia. It undergoes extensive metabolism in preclinical species and humans after oral administration and only a very small amount of administered dose is excreted as unchanged drug. In vitro studies using human liver microsomes have shown that the oxidative metabolism of ziprasidone is mediated primarily by CYP3A4. However, co-administration of ziprasidone with ketoconazole, a CYP3A4 inhibitor, showed only a modest increase in its exposure. Therefore, in vitro metabolism of ziprasidone was investigated in hepatic cytosolic fractions to further understand its clearance mechanisms in preclinical species and humans. The major metabolite from incubation of ziprasidone in cytosolic fractions of rat, dog and human was characterized by LC- MS/MS and found to be the product of reductive cleavage. Derivatization and H/D exchange were used to deduce that the addition of 2 hydrogen atoms had occurred at the benzisothiazole moiety. Further studies to determine the enzyme involved in the formation of this metabolite are currently in progress. The identification of this novel metabolite in cytosol has clarified the clearance mechanism of ziprasidone in humans and preclinical species.


Key words: CYP3A, cytochrome P450, drug-drug interactions, human CYP enzymes, human pharmacokinetics, metabolite identification, monooxygenases, structure elucidation


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