title: Brain extracellular γ-hydroxybutyrate concentrations are decreased by L-lactate in rats: role in the treatment of overdoses.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  L-lactate treatment increased GHB renal clearance from 1.4 ± 0.1 ml/min/kg (control) to 2.4 ± 0.2 and 4.7 ± 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 137 ± 12 min (control) to 91 ± 16 and 55 ± 5 min (low and high L-lactate, respectively). D-mannitol did not alter GHB TK/TD and did not alter L-lactate's effects on GHB TK/TD. L-lactate, but not D-mannitol, inhibited GHB uptake, and increased GHB efflux from RBE4 cells.
  
  
  CONCLUSIONS
  L-lactate decreases plasma and brain ECF concentrations of GHB, decreasing sedative/hypnotic effects.
authors: Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, State University of New York, Buffalo, Buffalo, New York 14214-8033, USA.
authors: Samuel A
authors: SA
authors: Roiko
authors: Nisha
authors: N
authors: Vijay
authors: Melanie A
authors: MA
authors: Felmlee
authors: Marilyn E
authors: ME
authors: Morris
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D062787:Drug Overdose; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D019344:Lactic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008353:Mannitol / Q000008:administration & dosage / Q000627:therapeutic use; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects*; D012978:Sodium Oxybate / Q000097:blood / Q000378:metabolism / Q000633:toxicity* / Q000652:urine
chemical_list: D006993:Hypnotics and Sedatives; D019344:Lactic Acid; D008353:Mannitol; D012978:Sodium Oxybate