title: Effects of probenecid on brain-cerebrospinal fluid-blood distribution kinetics of E-Delta 2-valproic acid in rabbits.
abstract: E-Delta 2-valproic acid (E-Delta 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-Delta 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-Delta 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-Delta 2-VPA to achieve a steady-state plasma concentration of 50 to 60 microg/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-Delta 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-Delta 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-Delta 2-VPA in the absence of a significant change in total or free steady-state plasma concentration. Mean E-Delta 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-Delta 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-Delta 2-VPA tissue concentrations is attributed primarily to inhibition of E-Delta 2-VPA efflux transport at the neural cell membrane, resulting in both intracellular trapping and greater tissue retention of E-Delta 2-VPA.
authors.affiliation: Department of Pharmaceutics, Schools of Pharmacy and Medicine, University of Washington, Seattle 98195-7610, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Scism
authors.forename: K M
authors.initials: KM
authors.lastname: Powers
authors.forename: A A
authors.initials: AA
authors.lastname: Artru
authors.forename: A C
authors.initials: AC
authors.lastname: Chambers
authors.forename: L
authors.initials: L
authors.lastname: Lewis
authors.forename: K K
authors.initials: KK
authors.lastname: Adkison
authors.forename: T F
authors.initials: TF
authors.lastname: Kalhorn
authors.forename: D D
authors.initials: DD
authors.lastname: Shen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000378:metabolism; D002946:Cisterna Magna / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007276:Injections, Intraventricular; D007700:Kinetics; D008297:Male; D010477:Perfusion; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D005229:Fatty Acids, Monounsaturated; C014168:2-propyl-2-pentenoic acid; D011339:Probenecid