Epilepsy Research
Volume 23, Issue 2 , Pages 95-104, March 1996

Effect of para-aminohippurate on the efflux of valproic acid from the central nervous system of the rabbit

  • Kimberly D.K. Adkison

      Affiliations

    • Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA
    • Glaxo Wellcome Research Institute, Five Moore Drive, Research Triangle Park, NC, USA
    • ,
  • Karen M. Powers

      Affiliations

    • Department of Anesthesiology, School of Medicine, University of Washington, Seattle, WA, USA
    • ,
  • Alan A. Artru

      Affiliations

    • Corresponding Author InformationCorresponding author. Dept. of Anesthesiology, University of Washington, 1959 NE Pacific St., Box 356540, Seattle, WA 98195-6540, USA. Tel.: (206) 685-2071; fax: (206) 543-2958
    • Department of Anesthesiology, School of Medicine, University of Washington, Seattle, WA, USA
    • ,
  • Danny D. Shen

      Affiliations

    • Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA

Received 15 September 1995; accepted 29 September 1995.

Abstract 

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14H]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.

Keywords:  Valproic acid, para-Aminohippurate, Organic anion transport, Blood-brain barrier, Choroid plexus

Abbreviations:  CNS = Central nervous system, CSF = Cerebrospinal fluid, EEG = Electroencephalogram, PAH = para-Aminohippurate, VPA = Valproic acid

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PII: 0920-1211(95)00092-5

Epilepsy Research
Volume 23, Issue 2 , Pages 95-104, March 1996

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