Evaluation of hepatotoxicity in rats of four synthetic valproic acid derivatives with potential anticonvulsant activity and low teratogenicity

ABSTRACT

The potential hepatotoxic effects of four synthetic valproic acid [VPA] derivatives likely to have a promising anticonvulsant activity with minimal teratogenic effects were studied in vivo and in isolated perfused livers of young rats using sodium valproate and 4-en valproic acid [4-en VPA], the main hepatotoxic metabolite of valproic acid, as positive controls. 4-en VPA [100 mg/kg] produced a significant elevation in serum transaminases [ALT and AST] and alkaline phosphatase with a decrease in total serum proteins, serum albumin and total serum bilirubin, while VPA [250 mg/kg] increased ALT and decreased total serum proteins and serum albumin when given i.p. to rats once daily for 8 days. Both compounds also produced fatty degeneration and vacuolar degeneration of the liver. When perfused in a concentration of 300 [micro]g/ml, into livers of young rats, sodium valproate and 4-en VPA produced significant elevation in ALT and AST activities in the perfusate. In both experiments, 4-en VPA was more hepatotoxic than VPA. On the other hand, three compounds namely R-2-n-propyl-4-hexynoic acid, [ +/- ] 4-methyl-2-n-propyl-4-pentenoic acid and [ +/- ] 2-isobutylpentenoic acid did not produce any significant effect on serum levels of ALT, AST, alkaline phosphatase, albumin and bilirubin when given to rats i.p. in a dose of 100 mg/kg once daily for 8 days. The three compounds did not produce histopathological alterations in the liver and did not increase ALT and AST activities in the perfusate of isolated liver when added to the perfusion fluid in a concentration of 300[micro]g/ml. The fourth compound, [ +/- ] 2-n-propyl-4-hexynoic acid, increased total serum bilirubin and decreased albumin/globulin ratio with no effects on liver histopathology or the other biochemical measurements in vivo and in vitro. These results should encourage the continuation of research on these compounds aiming to introduce new safe antiepileptic agents