Assessment of Valproic Acid Serum–Cerebrospinal Fluid Transport by Microdialysis

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Abstract
The systemic disposition and serum–cerebrospinal fluid (CSF) translocation of valproic acid (VPA) were examined in rats after administration of VPA as a bolus, as a continuous infusion, or with probenecid. VPA in CSF was monitored continuously by in vivo microdialysis. Both prolonged VPA infusion and probenecid pre-treatment increased the Km for saturable VPA elimination and decreased intrinsic hepatic clearance, perhaps due to competition of probenecid or accumulated VPA metabolites for glucuronidation or depletion of hepatic UDP-glucuronic acid. The CSF/serum VPA ratio increased rapidly initially, then decreased with time throughout the remainder of the experiment in all three groups. This time- and/ or concentration-dependent behavior suggested that the rate of CSF penetration increased disproportionately with increasing serum VPA and could be described by a kinetic model incorporating a concentration-dependent first-order rate constant for VPA influx into CSF. Under all experimental conditions, the VPA efflux from CSF appeared to be saturable; an increase in the Michaelis constant for efflux was observed following probenecid pretreatment and during VPA infusion, suggesting competitive inhibition of transport by probenecid and derived metabolites of VPA, respectively. The mechanisms responsible for asymmetric VPA transport between serum and CSF, in particular the apparent concentration-dependent change in the rate constant governing CSF penetration, remain to be elucidated.