QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.069682v1 311/1/92    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhattacharya, I. Articles by Boje, K. M. K. Search for Related Content PubMed PubMed Citation Articles by Bhattacharya, I. Articles by Boje, K. M. K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Club Drugs

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

GHB (-Hydroxybutyrate) Carrier-Mediated Transport across the Blood-Brain Barrier

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York

-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant, and date rape drug. Recreational abuse or overdose of GHB (or its precursors -butyrolactone or 1,4-butanediol) results in dose-dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, and death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier-mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacological agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier-mediated transport across the BBB consistent with a high-capacity, low-affinity transporter; averaged brain region parameters were V_max = 709 ± 214 nmol/min/g, K_m = 11.0 ± 3.56 mM, and CL_ns = 0.019 ± 0.003 cm³/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and -hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic anions (probenecid, benzoic, salicylic, and -cyano-4-hydroxycinnamic acid) significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and glutaric) and -aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well known substrate of the monocarboxylate transporter MCT1. These results are suggestive of GHB crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity.

Address correspondence to: Dr. Kathleen M. K. Boje, Department of Pharmaceutical Sciences, H517 Cooke-Hochstetter, University at Buffalo, Buffalo, NY 14260. E-mail: boje{at}buffalo.edu

This article has been cited by other articles:

				R. C. Lyon, S. M. Johnston, D. G. Watson, G. McGarvie, and E. M. Ellis Synthesis and Catabolism of {gamma}-Hydroxybutyrate in SH-SY5Y Human Neuroblastoma Cells: ROLE OF THE ALDO-KETO REDUCTASE AKR7A2 J. Biol. Chem., September 7, 2007; 282(36): 25986 - 25992. [Abstract] [Full Text] [PDF]

				Q. Wang and M. E. Morris The Role of Monocarboxylate Transporter 2 and 4 in the Transport of {gamma}-Hydroxybutyric Acid in Mammalian Cells Drug Metab. Dispos., August 1, 2007; 35(8): 1393 - 1399. [Abstract] [Full Text] [PDF]

				Q. Wang and M. E. Morris Flavonoids Modulate Monocarboxylate Transporter-1-Mediated Transport of {gamma}-Hydroxybutyrate in Vitro and in Vivo Drug Metab. Dispos., February 1, 2007; 35(2): 201 - 208. [Abstract] [Full Text] [PDF]

				Q. Wang, I. M. Darling, and M. E. Morris Transport of {gamma}-Hydroxybutyrate in Rat Kidney Membrane Vesicles: Role of Monocarboxylate Transporters J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 751 - 761. [Abstract] [Full Text] [PDF]