UPTAKE OF VALPROIC ACID INTO RAT-BRAIN IS MEDIATED BY A MEDIUM-CHAIN FATTY-ACID TRANSPORTER

The uptake of valproic acid (VPA) from blood into several brain region s was investigated using the in situ brain perfusion technique in the rat. The uptake kinetics of VPA exhibited partial saturability and tra ns-stimulation, which indicate the simultaneous presence of carrier-me diated transport and diffusion. The apparent Michaelis constant for th e saturable process ranged from 10 mM in the cortical regions to 23.5 mM in the thalamus. The uptake of radiotracer VPA was not inhibited by coperfusion of short-chain (less than or equal to C4) fatty acids and alpha-keto acids, which suggests that the short-chain monocarboxylic acid carrier at the blood-brain barrier is not involved in the uptake of VPA. In contrast, medium-chain (C6-C12) fatty acids inhibited the u ptake of radiotracer VPA. In addition, para-aminohippurate (PAH) inhib ited, whereas both cis- and trans-presence of medium-chain dicarboxyla tes markedly stimulated the cerebral uptake of radiotracer VPA. These observations suggest that the putative VPA transporter at the blood-br ain barrier may be an anion exchanger that operates in a manner simila r to that reported for the PAH transporter at the basolateral membrane of the renal tubular epithelium. However, unlike renal basolateral tr ansport of PAH, probenecid promoted rather than inhibited VPA uptake. Also, dicarboxylate stimulation of brain VPA uptake does not appear to be Na+ dependent. VPA exerted a reciprocal inhibition of octanoate up take into rat brain. Moreover, VPA was capable of inhibiting brain upt ake of short-chain monocarboxylic acids, including acetate, lactate an d pyruvate.