Brain Extracellular [gamma]-hydroxybutyrate Concentrations are Decreased by L-lactate in Rats: Role in the Treatment of Overdoses

• Published in: Pharmaceutical research 2013-05, Vol.30 (5), p.1338
• Main Authors: Roiko, Samuel A, Vijay, Nisha, Felmlee, Melanie A, Morris, Marilyn E
• Format: Article
• Language: English
• Subjects: Brain; Drug overdose; Pharmacology; Plasma; Rodents
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-0973-z

L-lactate represents a potential treatment for GHB overdose by inhibiting GHB renal reabsorption mediated by monocarboxylate transporters. Our objective was to assess the dose-dependence of L-lactate treatment, with and without D-mannitol, on GHB toxicokinetics/toxicodynamics (TK/TD). Rats were administered GHB 600 mg/kg i.v. with L-lactate (low and high doses), D-mannitol, or L-lactate (low dose) with D-mannitol. GHB-induced sleep time and GHB plasma, urine and brain extracellular fluid (ECF) concentrations (by LC/MS/MS) were determined. The effect of L-lactate and D-mannitol on the uptake and efflux of GHB was assessed in rat brain endothelial RBE4 cells. L-lactate treatment increased GHB renal clearance from 1.4â[euro][per thousand]±â[euro][per thousand]0.1 ml/min/kg (control) to 2.4â[euro][per thousand]±â[euro][per thousand]0.2 and 4.7â[euro][per thousand]±â[euro][per thousand]0.5 ml/min/kg after low and high doses, respectively, and reduced brain ECF AUC values to 65 and 25% of control. Sleep time was decreased from 137â[euro][per thousand]±â[euro][per thousand]12 min (control) to 91â[euro][per thousand]±â[euro][per thousand]16 and 55â[euro][per thousand]±â[euro][per thousand]5 min (low and high L-lactate, respectively). D-mannitol did not alter GHB TK/TD and did not alter L-lactateâ[euro](TM)s effects on GHB TK/TD. L-lactate, but not D-mannitol, inhibited GHB uptake, and increased GHB efflux from RBE4 cells. L-lactate decreases plasma and brain ECF concentrations of GHB, decreasing sedative/hypnotic effects.[PUBLICATION ABSTRACT]