Transport of valproic acid in the brain: Involvement of multiple organic anion transporters.

摘要

VPA is a commonly used anticonvulsant for a broad spectrum of epilepsies. It has been suggested that multiple carrier-mediated transport processes at the blood-brain barrier and brain parenchymal cell membrane can account for the rapid entry into the brain and yet low steady-state brain-to-blood concentration gradient of VPA. The overall objective of my dissertation research is to identify and characterize the brain transporters for VPA, particularly at the brain parenchymal cell membrane, through in vitro and in vivo studies. Based on available data in literature, I have elected to focus my investigation on members of the Multidrug Resistance Associated Protein (MRP), Organic Anion Transporter (OAT), Monocarboxylic Acid Transporter (MCT) and Anion Exchanger (AE) families.; MRP is a primary active organic anion efflux transporter. In intracerebral microdialysis studies in rabbits, we have demonstrated the presence of MRP-mediated efflux of VPA at the blood-brain-barrier and brain parenchymal cell membrane. The existence of energy-dependent efflux transport process in brain parenchyma was confirmed in primary cultures of rat neurons and astrocytes. Both cell types express mRNA and exhibit functional activity of rat MRP1. MRP inhibitors modestly enhanced cellular uptake of VPA in rat neurons and astrocytes, which suggests involvement of rat MRPs in the brain distribution of VPA. Using rat or human MRP1 transfected cell models, we found that VPA is transported by rat MRP1 but not by human MRP1.; OAT1 operates as an organic anion exchanger—exchanging organic anion for intracellular dicarboxylates. Using rat or human OAT1-transfected cells, we demonstrated that VPA is not a substrate of OAT1; however, it is a potent competitive inhibitor.; MCT is a proton-coupled monocarboxylic acid transporter. In primary cultures of rat neurons and astrocytes, we found that MCT mediated proton-dependent transport of VPA, although its contribution at physiological pH may be minor.; AE has been suggested to transport monocarboxylic acid in exchange for Cl− and/or HCO₃−. Our data with primary cultured rat neurons and astrocytes and AE3-transfected cells suggest that AE3 may mediate the efflux transport of VPA from neurons in the brain.