Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many psychotropic medications might cause prolongation of the QTc interval; however, antipsychotics have recently come under increasing scrutiny in this regard. Ziprasidone, a newly marketed second-generation antipsychotic, was initially delayed in approval by the FDA due to its propensity to prolong the QTc interval in patients with schizophrenia. While ziprasidone does prolong the QTc interval, safety, concomitant medication, and overdose data present little reason to consider ziprasidone a major risk factor for Torsades de Pointes thus far. The paucity of data regarding this agent, however, and its use in those with additional risk factors for QTc-interval prolongation are striking. The risk for this phenomenon has not been studied in patients with concomitant disease states that might be associated with QTc-interval prolongation or in those taking metabolic inhibitors which might inhibit aldehyde oxidase. Little is known about a major metabolic route of ziprasidone, oxidation by aldehyde oxidase. Finally, experience with other agents associated with QTc-interval prolongation raises the possibility that both the type and number of individuals studied to date might not be sufficient to reveal problems with ziprasidone. This paper will review the literature concerning real and theoretical implications of pharmacokinetic and pharmacodynamic interactions with ziprasidone, particularly with regard to these effects on the QTc interval.
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PMID:Ziprasidone and the QTc interval: pharmacokinetic and pharmacodynamic considerations. 1239 57

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.
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PMID:Ziprasidone metabolism, aldehyde oxidase, and clinical implications. 1523 43