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KD Adkison, AA Artru, KM Powers and DD Shen
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle.
The steady-state brain-to-free plasma concentration ratio of valproic acid (VPA) is well below unity, which suggests that it is efficiently removed from the central nervous system (CNS) by specialized transport processes. The purpose of this study was to determine whether probenecid (PBD)-sensitive anion transporters at the choroidal epithelium and brain capillary endothelium are involved in the clearance of VPA from the CNS of the rabbit. Unlabeled VPA was infused i.v. to achieve a steady-state plasma concentration while a tracer concentration of 3H-VPA was introduced into the ventricles by ventriculocisternal (VC) perfusion. In two treatment groups, PBD was administered by direct placement into the VC perfusate or by a combination of an i.v. priming dose and continuous infusion. In the control group, no other treatments were given. PBD administered by either route had no effect on the steady-state VC extraction of 3H-VPA (approximately 57%). Coadministration of PBD through the VC perfusate had no apparent effect on the blood-brain distribution of unlabeled VPA. In the i.v. PBD group, the concentration in the brain of systemically administered VPA increased 1.5- to 2-fold in all regions compared with that in control animals. Because neither the total nor the free plasma concentration of VPA was affected by PBD, the increase in brain VPA concentration reflected a blockade of VPA efflux across the brain capillary endothelium. These results suggest that PBD- sensitive transport at the brain capillary endothelium is the main route of VPA efflux from the CNS.
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