DOI: 10.1097/01.jcp.0000132446.58348.40
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PMID: 15232343
Issn Print: 0271-0749
Publication Date: 2004/08/01
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Excerpt
I read with interest the report in the February 2004 issue of the Journal by Harrigan et al1 on the effects of 6 antipsychotic drugs on the QTc interval. The authors point out that because CYP3A4 is responsible for only one third of ziprasidone's clearance, inhibition of this enzyme by ketoconazole caused no clinically meaningful change in the QTc interval. They further state that two thirds of ziprasidone clearance "is mediated by aldehyde oxidase, a pathway with no known clinically relevant inhibitors or inducers." In support of this statement, they cite a report by Beedham et al.2
Recently, however, an in vitro study of human liver aldehyde oxidase of which Beedham was one of the authors found substantial aldehyde oxidase inhibition (greater than 80%) by 36 of 239 drugs that were tested.3 These included phenothiazines, clozapine, olanzapine, amlodipine, erythromycin, ethinyl estradiol, raloxifene (most potent), and metoclopramide. The authors suggest that zaleplon which is metabolized by aldehyde oxidase might produce excessive sedation in the presence of one of the more potent inhibitors. While they do not mention ziprasidone, one must wonder whether some of the more potential aldehyde oxidase inhibitors could cause problematic QTc interval prolongation in combination with this drug, especially if CYP3A4 was also inhibited.
Clearly, in vitro data may not accurately predict what occurs in vivo. In fact, while ketoconazole was found to be one of the more potent aldehyde oxidase inhibitors and while it is also a potent CYP3A4 inhibitor, it only increased the Cmax of ziprasidone by a bit over 31% and did not significantly alter the QTc interval. Also, it should be noted that the study of inhibitors dealt only with aldehyde oxidase-catalyzed oxidation, whereas ziprasidone is metabolized by reduction. Whether these inhibitors also affect aldehyde oxidase-catalyzed reduction is not known, but should be subjected to future study.
