Ziprasidone metabolism, aldehyde oxidase, and clinical implications.
Ziprasidone (Geodon, Zeldox), a recently approved atypical antipsychotic agent for the treatment of schizophrenia, undergoes extensive metabolism in humans with very little (<5%) of the dose excreted as unchanged drug. Two enzyme systems have been implicated in ziprasidone metabolism: the cytosolic enzyme, aldehyde oxidase, catalyzes the predominant reductive pathway, and cytochrome P4503A4 (CYP3A4) is responsible for two alternative oxidation pathways. The involvement of two competing pathways in ziprasidone metabolism greatly reduces the potential for pharmacokinetic interactions between ziprasidone and other drugs. Because CYP3A4 only mediates one third of ziprasidone metabolism, the likelihood of interactions between ziprasidone and CYP3A4 inhibitors/ substrates is low. Furthermore, aldehyde oxidase activity does not appear to be altered when drugs or xenobiotics are coadministered. Aldehyde oxidase, a molybdenum-containing enzyme, catalyzes the oxidation of N-heterocyclic drugs such as famciclovir and zaleplon, in addition to reducing some agents such as zonisamide. Both reactions can occur simultaneously. Although in vitro inhibitors of aldehyde oxidase have been identified, there are no reported clinical interactions with aldehyde oxidase inhibitors or inducers. There is no evidence of genetic polymorphism in aldehyde oxidase, and thus it not surprising that ziprasidone exposure demonstrates unimodality in humans. Aldehyde oxidase is unrelated to the similarly named enzyme aldehyde dehydrogenase, which is predominantly responsible for the oxidation of acetaldehyde during ethanol metabolism. Consequently, it is unlikely that there would be any pharmacokinetic interaction between ethanol and ziprasidone.
Beedham
Christine
C
Department of Clinical Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire BD7 1DP, United Kingdom. c.beedham@bradford.ac.uk
Miceli
Jeffrey J
JJ
Obach
R Scott
RS
D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use
D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase