Probenecid-inhibitable efflux transport of valproic acid in the brain parenchymal cells of rabbits: a microdialysis study

Delivery of valproic acid (VPA) to the human brain is relatively inefficien t as reflected by a low brain-to-unbound plasma concentration ratio (less t han or equal to0.5) at steady state. Previous pharmacokinetic studies sugge sted that the unfavorable brain-to-plasma gradient is maintained by coupled efflux transport processes at both the brain parenchymal cells and blood-b rain barrier (BBB); one or both of the efflux transporters are inhibitable by probenecid. The present study in rabbits utilized microdialysis to measu re drug concentration in the brain extracellular fluid (ECF) of the cerebra l cortex during steady-state i.v. infusion with VPA alone or with VPA plus probenecid. Probenecid co-infusion elevated VPA concentration in the brain tissue surrounding the tip of the microdialysis probe to a greater extent t han in the ECF (230% versus 47%). Brain intracellular compartment (ICC) con centration was estimated. In control rabbits, the ICC concentration was 2.8 +/- 0.28 times higher than the ECF concentration. Probenecid co-infusion e levated the ICC-to-ECF concentration ratio to 4.2 +/- 0.44, which confirms the existence of an efflux transport system in brain parenchymal cells. The ECF-to-unbound plasma concentration ratio was well below unity (0.029), in dicating an uphill efflux transport of VPA across the BBB. Go-infusion of p robenecid did not have a significant effect on VPA efflux at the BBB as evi denced by a minimal change in the ECF-to-unbound plasma concentration ratio . This study suggests the presence of distinctly different organic anion tr ansporters for the efflux of VPA at the parenchymal cells and capillary end othelium in the brain. (C) 2000 Elsevier Science B.V. All rights reserved.