IN VIVO EFFECT OF SODIUM VALPROATE ON MOUSE LIVER

Abstract

39 The in vivo effect of sodium valproate (SV) on the activity of Uridine Diphospho-Glucuronosyl-Transferase (UDP-GT) and its hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally with SV in various doses (50 up to 800 mg/kg/day) for 6 consecutive days (dose response group) or in a standard dose of 300 mg/kg/day for various periods of time (2 up to 10 days, time response group), while controls were injected with normal saline. Serum valproic acid levels had a positive correlation to the dose (p<0.001) and duration of administration (p=0.006). A gradual increase of UDP-DT activity was observed in doses up to about 400 mg/kg/day, while in higher doses the enzyme activity gradually reduced. The time course of UDP-GT activity with the standard dose of 300 mg/kg/day had a progressive increase with maximum up to the 6th day and then a gradual reduction. Serum Alanine Aminotransferase (ALT) levels were not significantly different from those of the controls and were not correlated with the dose of SV. Hepatic necrosis, which was unrelated to dose or duration of drug administration, was found in 13% of the SV treated animals and in none of the controls. It is concluded that SV has a liver UDP-GT activity induction in an optimal dose and duration of treatment, over which it is gradually reduced, as well as an hepatotoxicity unrelated to the dose and time course.