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

Brain Res. 2000 Nov 24;884(1--2):77-86. doi: 10.1016/s0006-8993(00)02893-6.


Delivery of valproic acid (VPA) to the human brain is relatively inefficient as reflected by a low brain-to-unbound plasma concentration ratio (< or =0.5) at steady state. Previous pharmacokinetic studies suggested that the unfavorable brain-to-plasma gradient is maintained by coupled efflux transport processes at both the brain parenchymal cells and blood-brain barrier (BBB); one or both of the efflux transporters are inhibitable by probenecid. The present study in rabbits utilized microdialysis to measure drug concentration in the brain extracellular fluid (ECF) of the cerebral 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 than in the ECF (230% versus 47%). Brain intracellular compartment (ICC) concentration was estimated. In control rabbits, the ICC concentration was 2.8+/-0.28 times higher than the ECF concentration. Probenecid co-infusion elevated 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), indicating an uphill efflux transport of VPA across the BBB. Co-infusion of probenecid did not have a significant effect on VPA efflux at the BBB as evidenced by a minimal change in the ECF-to-unbound plasma concentration ratio. This study suggests the presence of distinctly different organic anion transporters for the efflux of VPA at the parenchymal cells and capillary endothelium in the brain.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport, Active / drug effects*
  • Biological Transport, Active / physiology
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / physiology
  • Brain / cytology
  • Brain / drug effects*
  • Brain / metabolism
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Drug Interactions / physiology*
  • Epilepsy / drug therapy
  • Extracellular Space / drug effects*
  • Extracellular Space / metabolism
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / metabolism
  • Ion Pumps / drug effects
  • Ion Pumps / metabolism
  • Male
  • Microdialysis / statistics & numerical data
  • Neuroglia / cytology
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Probenecid / pharmacology*
  • Rabbits
  • Valproic Acid / blood
  • Valproic Acid / pharmacokinetics*


  • Carrier Proteins
  • Ion Pumps
  • Valproic Acid
  • Probenecid