Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid

We examined the pharmacodynamics of valproate (VPA) and three structural analogues, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) in rats. A pentylenetetrazol (PTZ) infusion seizure model was used to determine threshold convulsive doses of PTZ; the increase in PTZ threshold dose after administration of test compound was taken as an index of anticonvulsant activity. Each of the compounds investigated antagonized PTZ-induced seizures, with MCCA evidencing the highest potency. Both CCA and MCCA appeared to have an approximate twofold advantage relative to VPA in protective index (i.e., the ratio of concentrations that produce toxicity to concentrations that produce anticonvulsant effect), based on a rotorod assay of neurotoxicity. Examination of the time course of PTZ antagonism indicated that there was significant dissociation between pharmacokinetics and pharmacodynamics of VPA, with a marked delay in production of maximal anticonvulsant activity. In contrast, only a slight delay in production of maximal protection against PTZ-induced seizures was observed for MCCA, and no delay was evident for CCA. The data indicate that the dynamics of anticonvulsant action differ between these low-molecular-weight carboxylic acids despite their similar chemical structures.