Clearance of valproic acid from brain tissue is believed to occur via a carrier-mediated system(s). The present study was designed to determine whether clearance was capacity-limited (saturable) and whether it occurred primarily at the choroid plexus. Ten rabbits were anesthetized with halothane and surgically prepared for ventriculocisternal perfusion. In group 1 (n = 5) valproic acid was added to blue dextran-containing mock cerebrospinal fluid (CSF) to achieve concentrations of 5, 20, 100, and 500 μg · ml-1. The mixture was infused through needles in both cerebral ventricles. The purpose of this group was to determine whether over a large range (100×) of valproic acid concentrations, clearance from CSF was capacity limited (saturable). In group 2 (n = 5) valproic acid concentrations were 3, 10, and 30 μg · ml-1 and infusion was into the left cerebral ventricle only. The purposes of this group were to determine (a) the magnitude of valproic acid clearance for the “clinical” range of valproic acid in CSF (10-30 μg · ml-1), and (b) whether clearance of valproic acid was changed by perfusion across a portion of the choroid plexus surface area (group 2) as compared with perfusion across the entire choroid plexus surface area (group 1). In both groups the percent extraction of valproic acid was calculated from the concentration ratio (valproic acid)out/(valproic acid)in corrected for the rate of CSF formation. In group 1 the percent extraction of valproic acid was 93 ± 2% (mean ± SD) at 5 μg · ml-1 and stabilized within the range of 58-70% (individual values) at the higher inflow concentrations of valproic acid. In group 2, the percent extraction of valproic acid stabilized within the range of 43-72% at the higher inflow concentrations. The mean percent extraction of valproic acid over the range of “clinical” concentrations of valproic acid in CSF (10 and 30 μg · ml-1) in group 2 was 55 ± 7%, not significantly different from that in group 1 (65 ± 3%) for 20 μg · ml-1. The finding in group 1 of decreased percent extraction of valproic acid with higher inflow concentrations indicates clearance of valproic acid from CSF was capacity limited (saturable). The finding of 55 ± 7% extraction in group 2 indicates substantial clearance at “clinical” valproic acid concentrations. The finding that percent extraction of valproic acid with biventricular perfusion (i.e., perfusion of valproic acid across the entire choroid plexus surface area) was not significantly different from that with univentricular perfusion (i.e., perfusion of valproic acid across a lower surface area of choroid plexus) indicates that the choroid plexus is not the principal route of efflux of valproic acid from CSF.
Address correspondence and reprint requests to Dr. A. A. Artru at Department of Anesthesiology, RN-10, University of Washington, School of Medicine, Seattle, WA 98195, U.S.A.
© 1994 by Lippincott Williams & Wilkins