Vol. 25, Issue 12, 1337-1346, 1997

Effects of Probenecid on Brain-Cerebrospinal Fluid-Blood Distribution Kinetics of E-²-Valproic Acid in Rabbits

Jamie L. Scism, Karen M. Powers, Alan A. Artru, Anne C. Chambers, Lydia Lewis, Kimberly K. Adkison, Thomas F. Kalhorn, and Danny D. Shen

Departments of Pharmaceutics (J.L.S., A.C.C., L.L., K.K.A., T.F.K., D.D.S.) and Anesthesiology (K.M.P., A.A.A.), Schools of Pharmacy and Medicine, University of Washington

E-²-valproic acid (E-²-VPA), a major active metabolite of VPA, has been proposed as an alternative to VPA because it is less hepatotoxic and is nonteratogenic. In rodents, VPA and E-²-VPA have a brain tissue/free plasma concentration ratio less than unity, which suggests rapid removal of the alkanoate anticonvulsants from the central nervous system. This study in rabbits employed a simultaneous iv infusion-ventriculocisternal (VC) perfusion technique to investigate the steady-state kinetics of E-²-VPA transport at the blood-brain barrier, the blood-cerebrospinal fluid (CSF) barrier, and the neural cell membrane. Probenecid (PBD) was coadministered to probe the mediation of transport by organic anion transporter(s). Rabbits in the control group (N = 6) received an iv infusion of E-²-VPA to achieve a steady-state plasma concentration of 50 to 60 µg/ml. Blood and cisternal outflow of mock CSF perfusate were continuously sampled. Midway through the experiment, the VC perfusate was switched to one containing [³H]E-²-VPA. At 225 min, the rabbits were sacrificed, and each brain was removed and dissected into ten regions. Rabbits in the PBD group (N = 9) received an iv infusion and VC perfusion as in the control group as well as concomitant iv infusion of the inhibitor. The mean steady-state VC extraction ratio for [³H]E-²-VPA did not differ between the control and PBD groups (63.7 ± 8.3% vs. 60.6 ± 9.6%), indicating the lack of a significant PBD-sensitive transport at the choroidal epithelium. Coadministration of PBD elevated brain concentration of cold E-²-VPA in the absence of a significant change in total or free steady-state plasma concentration. Mean E-²-VPA brain tissue/free plasma concentration ratios in the various brain regions were 3.5- to 5.2-fold higher in PBD-treated animals than in the controls. Significant increases (3.0- to 4.5-fold) in the mean brain tissue/cisternal perfusate concentration ratios were also observed. Compartmental modeling of the steady-state distribution data suggested that clearance of E-²-VPA from the brain parenchyma is governed jointly by efflux transporters at the neural cell membrane and brain capillary endothelium. Moreover, PBD-induced elevation of E-²-VPA tissue concentrations is attributed primarily to inhibition of E-²-VPA efflux transport at the neural cell membrane, resulting in both intracellular trapping and greater tissue retention of E-²-VPA.