Dose-dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high-dose valproic acid in rats
- Dose-dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high-dose valproic acid in rats
- 정병화; 김보준; 이민선; 이주현; 오주희; 이영주
- valproic acid; pharmacokinetics; dose-dependency; 4-ene-valproic acid; toxicity; 2,4-diene-valproic acid
- Issue Date
- Journal of applied toxicology : JAT
- VOL 30, NO 8, 775-778
- 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.
- Appears in Collections:
- KIST Publication > Article
- Files in This Item:
There are no files associated with this item.
- RIS (EndNote)
- XLS (Excel)
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.