Summary.

The cytotoxicity of two new valproic acid derivatives: N-(4-acetylphenyl-2-propylpentanamide) (E-31) and 4-((2-propylpentanoyl)aminobenzoic acid) (E-21), with proven anti-epileptic activity, are compared to valproic acid (VPA), using freshly isolated rat hepatocytes, a well-controlled biological model system in vitro with high metabolizing capacity. In rats, as in humans, VPA is metabolized in the liver by cytochrome P-450. As derivatives of VPA, we hypothesize that changes in their structure will result in differences in their metabolism and toxicity. Hepatocytes are treated for two hours with each compound at three concentrations: 0.1 mM; 0.3 mM and 1.0 mM. Effects of E-31 and E-21 on the cells are assessed by measuring cell viability, lactate dehydrogenase (LDH) activity and reduced glutathione level (GSH). E-31 and E-21 are less cytotoxic than VPA in isolated rat hepatocytes most pronounced at the highest concentration (1 mM). This is probably related to the different metabolism of the newly synthesized compounds, compared to VPA.