Reduction and methylation of ziprasidone by glutathione, aldehyde oxidase, and thiol S-methyltransferase in humans: an in vitro study

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
R Scott ObachAmin M Kamel

Abstract

In humans, approximately two-thirds of the metabolic clearance of ziprasidone proceeds through reduction of the N-S bond of the benzisothiazole moiety, which is followed by methylation of the resulting thiophenol to the major metabolite S-methyldihydroziprasidone. The objective of this study was to gain an understanding of the underlying mechanism of this clearance route. Incubation of ziprasidone in human liver cytosol yielded the reduction product dihydroziprasidone. Heating the cytosol prior to incubation prevented the reaction, and the reaction was saturable (K(M) = 3.9 µM; V(max) = 0.24 nmol/min/mg protein), supporting that it was enzyme catalyzed. It was partially stimulated by 2-hydroxypyrimidine and inhibited by menadione, supporting a role for aldehyde oxidase in this reaction. However, incubation of ziprasidone with reduced glutathione, even in the absence of cytosol, readily yielded dihydroziprasidone indicating that there is also a chemical reduction component to this clearance pathway. The pathway was reversible because incubation of dihydroziprasidone in cytosol or with oxidized glutathione in buffer yielded ziprasidone. The methylation of dihydroziprasidone was observed in human liver microsomes in the presence o...Continue Reading

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Citations

Feb 28, 2016·Archives of Toxicology·Mineko TeraoEnrico Garattini
Dec 9, 2014·Expert Opinion on Drug Metabolism & Toxicology·Roberto MandrioliLaura Mercolini
Mar 9, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hlaing H MawAaron M Teitelbaum
Apr 16, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Miho KazuiAtsushi Kurihara
Sep 8, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mailys De Sousa MendesVenkatesh Pilla Reddy
Mar 3, 2021·Scientific Reports·Benjamin J MaldonatoRheem A Totah
Aug 7, 2019·Journal of Medicinal Chemistry·Nenad ManevskiFrancesca Toselli

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