Drugs That Inhibit Oxidation Reactions Catalyzed by Aldehyde Oxidase Do Not Inhibit the Reductive Metabolism of Ziprasidone to its Major Metabolite, S-Methyldihydroziprasidone

Abstract

Ziprasidone is metabolized in 2 sequential reactions to S-methyldihydroziprasidone, a major circulating metabolite of ziprasidone in humans. Aldehyde oxidase catalyzes the first reaction, a reduction of the benzisothiazole ring to dihydroziprasidone, and thiol methyltransferase catalyzes the second reaction, methylation of the thiophenol group to yield S-methyldihydroziprasidone. The conversion of ziprasidone to S-methyldihydroziprasidone was observed in S9 fraction from human livers when supplemented with S-adenosylmethionine. In this report, 36 drugs and other compounds that had been previously identified as in vitro inhibitors of human liver aldehyde oxidase were assessed for their potential to inhibit ziprasidone metabolism to S-methyldihydroziprasidone. Of these drugs, only ketoconazole, ondansetron, and tamoxifen demonstrated any inhibition. From these findings, it can be concluded that most known inhibitors of human aldehyde oxidase-catalyzed oxidation reactions are not inhibitors of ziprasidone reductive metabolism. Aldehyde oxidase oxidation and reduction reactions appear to have different sensitivities to inhibitors. These data suggest that it is unlikely that aldehyde oxidase inhibitors could cause increases in ziprasidone exposure in the clinic.