Age-related differences in susceptibility to toxic effects of valproic acid in rats.
A multi-age rat model was evaluated as a means to identify a potential age-related difference in liver injury following exposure to valproic acid (VPA), a known pediatric hepatotoxic agent. Different age groups of Sprague-Dawley (SD) rats (10-, 25-, 40-, 80-day-old) were administered VPA at doses of 160, 320, 500 or 650 mg kg(-1) (i.p.) for 4 days. Animals from all age groups developed toxicity after treatment with VPA; however, the patterns of toxicity were dissimilar within each age group. The high dose of VPA caused significant lethality in 10- and 25-day-old rats. All doses of VPA caused decrease in the platelet counts (10-, 25-day-old rats) and the rate of growth (40-day-old rats) and increases in the urine creatine concentration (high dose, 80-day-old rats). VPA induced hepatic and splenic alterations in all age groups. The most severe lesions were found mostly in 10- and 80-day-old rats. Significant changes in blood urea nitrogen, alanine aminotransferase and alkaline phosphatase were observed in 10-day-old pups after treatment with low doses of VPA. The highest VPA dose caused significant decreases in the levels of serum total protein (40- and 80-day-old rats). Principal component analysis of spectra derived from terminal urine samples of all age groups showed that each age group clusters separately. In conclusion, this study showed that the vulnerability profile of each age group was different indicating that a multi-age pediatric animal model is appropriate to assess more completely age-dependent changes in drug toxicity.
Espandiari
Parvaneh
P
FDA, Center for Drug Evaluation and Research, Silver Spring, MD 20993, USA. parvaneh.espandiari@fda.hhs.gov
Zhang
Jun
J
Schnackenberg
Laura K
LK
Miller
Terry J
TJ
Knapton
Alan
A
Herman
Eugene H
EH
Beger
Richard D
RD
Hanig
Joseph P
JP
D000375:Aging / Q000502:physiology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D005260:Female; D008099:Liver / Q000187:drug effects / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008660:Metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; D014635:Valproic Acid; D000410:Alanine Transaminase