Brain uptake of the drug of abuse γ-hydroxybutyric acid in rats.
γ-Hydroxybutyric acid (GHB) is an endogenous compound and a substrate for the ubiquitous monocarboxylate transporter (MCT) family. GHB is also a drug of abuse due to its sedative/hypnotic and euphoric effects, with overdoses resulting in toxicity and death. The goal of this study was to characterize the distribution of GHB into the brain using in vivo microdialysis and in vitro uptake studies and to determine concentration-effect relationships for GHB in a rat animal model. GHB was administered to rats (400, 600, and 800 mg/kg i.v.), and blood, dialysate, and urine were collected for 6 h post-GHB administration. The GHB plasma and extracellular fluid (ECF) concentration-time profiles revealed that GHB concentrations in ECF closely followed plasma GHB concentrations. Sleep time increased in a dose-dependent manner (91 ± 18, 134 ± 11, and 168 ± 13 min, for GHB 400, 600, and 800 mg/kg, respectively). GHB partitioning into brain ECF was not significantly different at 400, 600, and 800 mg/kg. GHB uptake in rat and human brain endothelial cells exhibited concentration dependence. The concentration-dependent uptake of GHB at pH 7.4 was best-fit to a single-transporter model [K(m) = 18.1 mM (human), 23.3 mM (rat), V(max) = 248 and 258 pmol · mg(-1) · min(-1) for human and rat, respectively]. These findings indicate that although GHB distribution into the brain is mediated via MCT transporters, it is not capacity-limited over the range of doses studied in this investigation.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 527 Hochstetter Hall, Buffalo, NY 14260, USA.
Samuel A
SA
Roiko
Melanie A
MA
Felmlee
Marilyn E
ME
Morris
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002461:Cell Line, Transformed; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood / Q000378:metabolism*; D013287:Illicit Drugs / Q000097:blood / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D006885:Hydroxybutyrates; D013287:Illicit Drugs; D027501:Monocarboxylic Acid Transporters; C111420:4-hydroxybutyric acid