The purpose of the present study was to evaluate the acute anticonvulsant effects of caprylic acid (CA), the main constituent of the medium-chain triglyceride ketogenic diet (MCT KD), in seizure tests typically used in screening for potential antiepileptic drugs in mice. Pharmacodynamic and pharmacokinetic interactions between CA and valproate (VPA) were also investigated. CA (p.o.) and VPA (i.p.) were administered 30 min before testing. Acute effects on motor coordination were assessed in the chimney test. Total plasma and brain concentrations of CA and VPA, when administered alone or in combination, were determined by high performance liquid chromatography. CA (10-30 mmol/kg) increased the threshold for i.v. pentylenetetrazole-induced myoclonic and clonic convulsions, but not tonic convulsions. CA (5-30 mmol/kg) increased the threshold for 6-Hz psychomotor seizures but was ineffective in the maximal electroshock seizure threshold test. CA (10-60 mmol/kg p.o.) impaired motor performance in the chimney test (TD(50) value, 58.4 mmol/kg). Increasing doses of CA (5-30 mmol/kg) produced proportional increases in plasma and brain exposure with constant brain/plasma partitioning. CA increased anticonvulsant potency of VPA in the maximal electroshock seizure and 6-Hz seizure tests. Co-administration of CA and VPA had no effect on brain and plasma concentrations of either compound. In summary, CA exerts acute anticonvulsant effects and potentiates the anticonvulsant effect of VPA at doses that result in plasma exposures comparable to those reported in epileptic patients on the MCT KD. Thus, this acute anticonvulsant property of CA may benefit and add to the overall clinical efficacy of the MCT KD.