The antiepileptic drug valproic acid (VPA) is a branched-chain fatty acid with unique pharmacodynamic properties. Unlike other commonly used antiepileptics, the anticonvulsant activity of VPA is poorly correlated with plasma drug concentration. Recent studies in neurosurgical patients showed that, during chronic VPA therapy, the concentrations of VPA in human brain were much lower than either the total or unbound serum drug concentrations. More significant is the fact that the steady-state brain- to-serum concentration ratios varied widely between individuals. It appears that the failure to demonstrate a clearly definable relationship between clinical effect and circulating concentration of VPA in patients with epilepsy may be related to the unusually large interindividual variation in blood-brain partitioning of the drug. The overall objective of this project is to investigate the cause of this low and variable distribution of VPA into brain. We hypothesize that (1) the translocation of VPA across blood-brain and blood-cerebrospinal fluid (CSF) barriers is mediated by membrane transport carriers for endogenous carboxylic acids, (2) individual differences in the physiologic regulation of these transport processes accounts for the observed variation in CNS distribution of VPA between patients, and (3) the low brain-to-blood concentration gradient of VPA is due to an asymmetry in drug transport between brain and blood. Thus, a series of in vivo and in vitro studies in animal models are proposed to identify and characterize the putative transport carriers for VPA and its 2-unsaturated analog (E)-delta2-VPA. The latter compound is currently under development as a second generation alkanoate anticonvulsant. We will test the specific hypothesis that VPA and (E)- delta2-VPA are shuttled across the brain capillary endothelium by the monocarboxylic acid (MCA) transporter, which mediates the exchange of ketone bodies and lactate between blood and brain. Cerebrovascular transport studies will be performed using the in situ brain perfusion technique in rats and the in vitro bovine brain microvessel endothelial cell culture model. Evidence that the branched-chain fatty acids and endogenous MCAs share the same endothelial transport system will be sought. The contribution of an efflux pathway at the choroidal epithelium will be investigated by in vitro uptake studies with isolated rabbit choroid plexus and by transepithelial transport studies with an in situ lateral ventricle choroid plexus preparation in the rabbit. Specifically, we will test if the medium, branched-chain fatty acids are transported by the organic anion exchanger at the brush-border membrane of the choroid plexus. Information on the CNS transport of branched-chain fatty acids may be useful in developing mechanism-based strategies for improving the brain delivery of alkanoate antiepileptics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS030738-05A1
Application #
2396568
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Jacobs, Margaret
Project Start
1992-05-01
Project End
2000-06-30
Budget Start
1997-09-30
Budget End
1998-06-30
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Gibbs, John P; Adeyeye, Moji Christianah; Yang, Ziping et al. (2004) Valproic acid uptake by bovine brain microvessel endothelial cells: role of active efflux transport. Epilepsy Res 58:53-66
Yang, Ziping; Li, Cheryl S W; Shen, Danny D et al. (2002) Cloning and characterization of the rat multidrug resistance-associated protein 1. AAPS PharmSci 4:E15
Scism, J L; Powers, K M; Artru, A A et al. (2000) Probenecid-inhibitable efflux transport of valproic acid in the brain parenchymal cells of rabbits: a microdialysis study. Brain Res 884:77-86
Adkison, K D; Shen, D D (1996) Uptake of valproic acid into rat brain is mediated by a medium-chain fatty acid transporter. J Pharmacol Exp Ther 276:1189-200
Adkison, K D; Powers, K M; Artru, A A et al. (1996) Effect of para-aminohippurate on the efflux of valproic acid from the central nervous system of the rabbit. Epilepsy Res 23:95-104
Adkison, K D; Ojemann, G A; Rapport, R L et al. (1995) Distribution of unsaturated metabolites of valproate in human and rat brain--pharmacologic relevance? Epilepsia 36:772-82
Adkison, K D; Artru, A A; Powers, K M et al. (1995) Role of choroid plexus epithelium in the removal of valproic acid from the central nervous system. Epilepsy Res 20:185-92
Naora, K; Shen, D D (1995) Mechanism of valproic acid uptake by isolated rat brain microvessels. Epilepsy Res 22:97-106
Arends, R H; Zhang, K; Levy, R H et al. (1994) Stereoselective pharmacokinetics of stiripentol: an explanation for the development of tolerance to anticonvulsant effect. Epilepsy Res 18:91-6
Adkison, K D; Artru, A A; Powers, K M et al. (1994) Contribution of probenecid-sensitive anion transport processes at the brain capillary endothelium and choroid plexus to the efficient efflux of valproic acid from the central nervous system. J Pharmacol Exp Ther 268:797-805