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The role of pharmacokinetics, drug interactions and pharmacogenetics in the acquired long QT syndrome

J.L. Bauman*

Departments of Pharmacy Practice and Medicine, University of Illinois at Chicago, U.S.A.

* Correspondence: Jerry L. Bauman, Pharm D, FACC, Departments of Pharmacy Practice and Medicine, Section of Cardiology, University of Illinois at Chicago, 833 Wood Street m/c 886, Chicago, Illinois 60612, U.S.A.

Abstract

Biotransformation of drugs is accomplished by phase I (P450 enzymes) and phase II metabolism (conjugation) predominantly in the small intestine and liver. As are most drugs, commercially available non-antiarrhythmic agents that have been reported to cause torsade de pointes are primarily metabolized by cytochrome P450 (CYP) isozymes 3A4 and 2136. It is possible that polymorphisms and heritable variations in the activity of these isozymes place an individual administered select potassium channel blocking drugs at a genetic risk for the development of torsade de pointes. A more common scenario, however, is that drug interactions, usually involving agents such as erythromycin that block CYP3A4, have led to this form of proarrhythmia. In the recent past, a significant number of highly visible drug withdrawals have occurred (e.g. terfenadine, asthemizole, cisapride) all with a consistent theme: parent drugs that block the rapid component of the delayed rectifier given for non-life-threatening disorders and are metabolized by CYP3A4 have been linked to torsade de pointes and reports of death have ensued when the drug was combined with inhibitors of this isozyme (e.g. erythromycin, ketoconazole, grapefruit juice). Because of these situations and their resultant impact upon the health of the public, it seems prudent that all new entities under investigation (and their significant metabolites) be screened for the potential to cause torsade de pointes.

Key Words: Drug metabolism • cytochrome P450 enzymes • torsade de pointes • potassium blockers • drug interactions • pharmacogenetics

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This Article
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