In vivo effect of sodium valproate on mouse liver

The in vivo effect of sodium valproate (SV) on the activity of uridine diph osphate glucuronosyltransferase:(UDP-GT) and hepatotoxicity in the mouse li ver 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-respo nse group) or at a standard dose of 300 mg/g per day for 2-10 days (time-re sponse group), whereas the controls were injected:with normal saline. Valpr oic acid levels had a positive correlation to the dose (P < 0.001) and dura tion of drug administration (P = 0.006). A gradual increase in UDP-GT activ ity 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 o f UDP-GT activity at the standard dose of 300 mg/kg per day increased progr essively, with a maximum up to the sixth day and then had a gradual reducti on. Hepatic necrosis (which was unrelated to the dose or the duration of dr ug administration) was found in 13% of the SV-treated animals and in none o f 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 g radually reduced. SV also causes hepatotoxicity unrelated to dose and:time course.