Characterization of a novel metabolite intermediate of ziprasidone in hepatic cytosolic fractions of rat, dog, and human by ESI-MS/MS, hydrogen/deuterium exchange, and chemical derivatization.
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, coadministration 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 liquid chromatography-tandem mass spectrometry and found to be the product of reductive cleavage. Derivatization and hydrogen/deuterium exchange were used to deduce that the addition of two 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.
Miao
Zhuang
Z
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA.
Kamel
Amin
A
Prakash
Chandra
C
D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism*; D003903:Deuterium; D004285:Dogs; D006801:Humans; D006859:Hydrogen; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013844:Thiazoles / Q000493:pharmacokinetics*
D014150:Antipsychotic Agents; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System; D003903:Deuterium; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human