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Pharmacokinetics, tissue distribution and serum protein binding of (E,Z)-2,3’-diene VPA in rats Moshenko, Janice Lynn


Valproic acid (VPA) is a broad spectrum anticonvulsant drug presently used for the management of various seizure disorders. Despite its reputation for being a relatively safe antiepileptic, it has been characterized by two potentially fatal side effects, namely hepatotoxicity and teratogenicity. Hence, the development of analogues of VPA lacking the toxic side effects but possessing the desired attributes of conventional anticonvulsants would be of great benefit therapeutically. One interesting observation with VPA therapy is a delayed anticonvulsant effect that occurs after discontinuation of VPA and after VPA has been cleared from the systemic circulation. Since VPA is extensively metabolized and its metabolites have been shown to possess anticonvulsant activity, the possibility exists that one or more of VPA's active metabolites may be contributing to the prolongedpharmacological activity of VPA. One such metabolite, (E,Z)-2,3'-diene VPA, has been of interest in our laboratory. This diene was preferentially found in rat brain after administration of VPA. Preliminary investigations with this compound demonstrated that it possessed equivalent anticonvulsant activity to VPA using the PTZ seizure test in rats and mice, and minimal muscle spasticity and sedative effects when compared to VPA. These studies suggested that this diene may have potential as an alternative medication to VPA. Therefore, investigations into the pharmacokinetics and disposition of (E,Z)-2,3'-diene VPA in rats were conducted in order to assess the diene's contributions to VPA activity and its potential as an alternative medication to VPA.

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