In vivo effect of sodium valproate on mouse liver.
The in vivo effect of sodium valproate (SV) on the activity of uridine diphosphate glucuronosyltransferase (UDP-GT) and hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally (IP) with SV at doses varying from 50 to 800 mg/kg per day, for six consecutive days (dose-response group) or at a standard dose of 300 mg/g per day for 2-10 days (time-response group), whereas the controls were injected with normal saline. Valproic acid levels had a positive correlation to the dose (P < 0.001) and duration of drug administration (P = 0.006). A gradual increase in UDP-GT activity was observed in doses of up to approximately 400 mg/kg per day, whereas in higher doses the enzyme activity gradually decreased. The time course of UDP-GT activity at the standard dose of 300 mg/kg per day increased progressively, with a maximum up to the sixth day and then had a gradual reduction. Hepatic necrosis (which was unrelated to the dose or the duration of drug administration) was found in 13% of the SV-treated animals and in none of the controls. We conclude that at an optimal dose (300-400 mg/kg per day) and at a time course of 6 days, SV causes liver UDP-GT induction, whereas in higher doses and longer duration of administration, UDP-GT activity is gradually reduced. SV also causes hepatotoxicity unrelated to dose and time course.
Roma-Giannikou
E
E
1st Department of Pediatrics, Athens University, Aghia Sophia Children's Hospital, Greece.
Syriopoulou
V
V
Kairis
M
M
Pangali
A
A
Sarafidou
J
J
Constantopoulos
A
A
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D013997:Time Factors; D014635:Valproic Acid / Q000097:blood / Q000494:pharmacology*
D000927:Anticonvulsants; D014635:Valproic Acid; D014453:Glucuronosyltransferase; D000410:Alanine Transaminase