The E-isomer of 2-unsaturated valproate (E-delta 2-VPA) is a pharmacologically active metabolite of VPA that is less teratogenic and hepatotoxic than its saturated precursor. To assess potential use of E-delta 2-VPA as an alternate to VPA, a dose-response study comparing the anticonvulsant activity and neurotoxicity of E-delta 2-VPA and VPA was conducted in rats using the intravenous (i.v.) pentylenetetrazol (PTZ)-infusion threshold seizure model. Assay of drug in whole brain and plasma allowed comparison of the drug concentration-effect relationships and the brain distribution characteristics of the two compounds. E-delta 2-VPA was two to three times more potent than VPA in elevating the clonic seizure threshold of PTZ, in reference to either plasma or whole-brain drug concentrations. Furthermore, much steeper response curves were observed with E-delta 2-VPA as compared with VPA. Within the pharmacologic concentration range (defined as EC25 to EC75), E-delta 2-VPA was less neurotoxic than VPA as assessed by behavioral tests. Therefore, E-delta 2-VPA has a much more favorable protective index than VPA. At low doses, the concentration ratios of brain to plasma for both E-delta 2-VPA and VPA increased markedly with increasing plasma drug concentration. E-delta 2-VPA and VPA were previously shown to exhibit saturable binding to rat plasma proteins. If we assume that uptake of drug into the CNS is limited to the equilibrium plasma free fraction in the brain microvasculature, much of the nonlinear brain distribution features of VPA could be accounted for by saturable drug plasma protein binding. On the other hand, more complex kinetics involving simultaneous saturation of plasma protein binding and blood-to-brain transport are proposed to explain the brain distribution of the unsaturated compound. In addition, the brain-to-free drug concentration ratios for both E-delta 2-VPA and VPA were below unity at high drug-concentration range, consistent with the presence of an efficient efflux mechanism of these compounds from brain.