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Time-course studies on the distribution and metabolism of valproate (VPA) in rat brain, liver, and kidney, after intraperitoneal injection of a mixture of [14C]VPA and [3H]VPA, showed that: (1) maximal amount of radioactivity in the various tissues was observed after 30 min from the time the drug was administered; (2) at 30 min the distribution of labeled VPA in brain, liver, and kidney was 17%, 64%, and 19% of the total radioactivity, respectively; (3) at 24 hr more than 97% of the total radioactivity was lost from the tissues and the 14C/3H ratios increased significantly with time. Studies on the regional distribution of the drug showed that it is relatively homogeneously distributed. Studies on the subcellular distribution of the drug showed that it is associated mostly with the soluble and mitochondrial fractions, with little radioactivity in the myelin and symaptosomal fractions. Radiochromatography of VPA metabolites in perchloric acid extracts from brain, liver, and kidney revealed the presence of four metabolites. VPA was not incorporated into phospholipids of the neuronal membranes. Furthermore, it had no significant effects on Mg2+-ATPase and (Na+ + K+)-ATPase in synaptosomes and microsomes obtained either from control or from rats injected with VPA. It was concluded that this antiepileptic drug does not appear to act through its incorporation into neuronal membrane or through its action of the Na+ pump.

Studies were conducted on the effects of antiepileptic drugs on the acetylcholine-stimulated 32P labeling of phospholipids in rat brain synaptosomes. Of the four antiepileptic drugs investigated in the present study, namely phenytoin, carbamazepine, phenobarbital, and valproate, only phenytoin blocked the acetylcholine-stimulated 32P labeling of phosphatidylinositol and phosphatidic acid, and the acetylcholine-stimulated breakdown of polyphosphoinositides. Phenytoin alone, like atropine alone, had no effect on the 32P labeling of phospholipids nor on the specific radioactivity of [32P]ATP. Omission of Na+ drastically reduced both the 32P labeling of synaptosomal phospholipids and the specific radioactivity of [32P]ATP and furthermore it significantly decreased the phosphoinositide effect. It was concluded that certain antiepileptic drugs, such as phenytoin, could exert their pharmacological actions through their antimuscarinic effects. In addition the finding that phenytoin, which acts to regulate NA+ and Ca2+ permeability of neuronal membranes, also inhibited the phosphoinositide effects in synaptosomes, support the conclusions that Ca2+ and Na+ are probably involved in the molecular mechanism underlying this phenomenon in excitable tissues.U

(1) Nerve-ending particles isolated from crude mitochondrial preparations from rat brain by discontinuous Ficoll density gradient ultracentrifugation were shown to possess a Mg2+ and energy-dependent transport system for Na+. (2) Ouabain or iodoacetate plus cyanide exerted an inhibitory effect on the outflux but not the influx of Na+. (3) When K+ was added to a medium containing particles loaded with Na+ (22Na), an immediate release of Na+ from these particles was observed; this suggests the existence of a Na+-K+ exchange transport system. (4) The K+ effect was inhibited by 10(-4) M-ouabain only at low (about 3.3 mM), but not at high (20 mM), K+ concentrations. (5) The uptake and release of Na+ by the nerve-ending particles were found to be temperature-dependent. (6) Only nerve-ending particles with intact synaptosomal membranes were found to transport Na+ actively.