In vivo effect of sodium valproate on mouse liver

Abstract

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.

In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates

“…Although valproic acid plasma levels were not evaluated in this study, reported valproic acid levels in a comparable mouse model treated with 500 mg/kg/d resulted in valproic acid plasma concentrations of 3 mmol/L. The reported ED 50 for seizure control in this model was f2 mmol/L (13,14). In contrast, recommended concentrations for seizure control or for the treatment of mania in adults are 50 to 125 Amol/L/mL (0.3 -0.9 mmol/L; Food and Drug Administration package insert).…”

“…Concentrations of 500 mg/kg/d divided in two doses were tolerable but showed a relative weight gain retardation when compared with saline-treated mice. Reports from other investigators in this mouse model suggested excessive toxicities at 800 mg/kg/d (13,14). The reported LD 50 for epirubicin in mice was 16 mg/kg (15).…”

Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

“…6B, tumor progression was significantly inhibited (P < 0.05) in animals treated with VPA followed by epirubicin compared with mice treated with saline, epirubicin, or VPA alone. The concentration of VPA used in this study reflects plasma concentrations of f3 mmol/L (26,27). VPA plasma concentrations typically used for the chronic treatment of migraine headaches or seizures range from 0.3 to 1.1 mmol/L [Food and Drug Administration (FDA) package insert].…”

Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development

“…Diminished BW gain was detected in the group exposed to the highest tested dose (400 mg/kg/day), but prolonged treatment could also contribute to the observed effect. Clinical findings do not consider the dose of 1000 mg/day (simulated in our study by 200 mg/kg/day) harmful to the health of adult patients; however, species differences in the pharmacokinetics of VPA and the daily regimen of administration must be taken into account when comparing human and rodent data [39][40][41]. VPA usage in women is mainly associated with polycystic ovary syndrome (weight gain, increase in androgen levels) and sub-fertility [42].…”