Dose-dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high-dose valproic acid in rats

Title
Dose-dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high-dose valproic acid in rats
Authors
정병화김보준이민선이주현오주희이영주
Keywords
valproic acid; pharmacokinetics; dose-dependency; 4-ene-valproic acid; toxicity; 2,4-diene-valproic acid
Issue Date
2010-12
Publisher
Journal of applied toxicology : JAT
Citation
VOL 30, NO 8, 775-778
Abstract
It has been reported that urinary excretion of two metabolites of valproic acid (VPA), 4-ene-valproic acid (4-VPA) and 2,4-diene-valproic acid (2,4-VPA), increased exponentially with the administration of high doses ofVPA, and this increased formation of toxic metabolites could be related to VPA hepatotoxicity in humans. The aim of this study was to investigate whether the plasma level of 4-VPA and 2,4-VPA in rats corresponds to the urinary data for the same metabolites in humans. After the oral administration of VPA at doses of 20, 100 and 500 mg kg-1 in rats, the AUC0–24 h, 4-VPA/AUC0–24 h, VPA ratios (0.0399, 0.0120 and 0.0100 for 20, 100 and 500 mg kg-1, respectively) and AUC0–24 h, 2,4-VPA/AUC0–24 h, VPA ratios (0.00104, 0.00201 and 0.00141, respectively) did not increase with increasing doses of VPA in rats. Thus, the plasma exposure of toxic metabolites normalized by dose remained unchanged (for 2,4-VPA) or even decreased (for 4-VPA) following high-dose VPA administration; this contradicts the findings of previous studies. Our results suggest that toxicity induced by high doses of VPA cannot be explained by a nonlinear increase of toxic metabolites in rats.
URI
http://pubs.kist.re.kr/handle/201004/39220
ISSN
0260-437X
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