Inhibitory effect of valproate on weak organic acid uptake in rat renal proximal tubules

The effects of an antiepileptic drug, valproic acid (VPA), on transport mechanisms involved in renal excretion of anionic xenobiotics were investigated on rat renal proximal tubules in vitro. It was found that VPA (0.1-1 mM) dose dependently inhibited the baseline uptake of a marker organic anion, fluorescein, in the tubules. The inhibition could not be exclusively accounted for by competition between VPA and fluorescein. Taking into account a proposed relationship between the weak organic anion uptake and ammoniagenesis, the influence of VPA (0.5 mM) on the effects of glutamine and glutamate (both at 5 mM) on fluorescein uptake and ammonia production were examined. Glutamine stimulated ammonia production by the tubules, with the glutamine-induced ammoniagenesis being further augmented by VPA, while glutamate failed to affect the basal ammoniagenesis. Both glutamine (5 mM) and glutamate (5 mM) slightly inhibited fluorescein uptake, with the inhibitory effects not modified by VPA. Thus, there was no coincidence in the effects of VPA on organic anion uptake and renal ammoniagenesis. At the same time, the inhibitory effect of VPA (0.5 mM) on fluorescein uptake was largely overcome by addition of pyruvate (5 mM) to the incubation medium. In addition, VPA strongly inhibited glucose production from pyruvate. A known modulator of pyruvate metabolism, dichloroacetic acid (DCA, 1 mM), also inhibited fluorescein uptake, although its inhibitory effect was less pronounced than that of VPA. Both inhibitors failed to alter the tissue content of alpha-ketoglutarate or lactate but did slightly augment the pyruvate level. The inhibitory effects of VPA and DCA on the baseline fluorescein uptake were not additive, suggesting their similar intracellular targeting. It is assumed that the inhibitory effect of VPA on baseline fluorescein uptake in rat renal proximal tubules in vitro may be associated with its action on pyruvate metabolism.