Transport of valproate at intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells: Mechanism and substrate specificity

To reach its target cells, the antiepileptic drug valproate has to cross both the intestinal epithelial barrier and the blood–brain barrier in intact form as well as in sufficient amounts. This study was performed to characterize the epithelial transport of valproate at intestinal (Caco-2) and at blood–brain barrier (RBE4) cells. At both cell types, uptake of [3H]valproate was independent of inwardly directed Na+, Ca2+, Mg2+, K+ or Cl− gradients. Uptake was, however, strongly stimulated by an inwardly directed H+ gradient. The cells accumulated valproate against a concentration gradient and the uptake rate of valproate was saturable with Kt values of 0.6 and 0.8 mM. At Caco-2 cell monolayers, the total apical-to-basolateral flux of [3H]valproate exceeded the basolateral-to-apical flux 14-fold. Various monocarboxylic acids like salicylate, benzoate, acetate, propionate, butyrate, hexanoate, diclofenac and ibuprofen inhibited [3H]valproate uptake at both cell types. Lactate and pyruvate inhibited valproate uptake at RBE4 cells but not at Caco-2 cells. We conclude that valproate is accumulated in intestinal cells against a concentration gradient by the activity of a specific H+-dependent DIDS-insensitive transport system for monocarboxylates not identical with monocarboxylate transporter 1 (MCT1). The passage of valproate across the blood–brain barrier is very likely mediated by MCT1.