Journal
PHARMACEUTICAL RESEARCH
Volume 30, Issue 5, Pages 1338-1348Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-013-0973-z
Keywords
lactate; microdialysis; monocarboxylate transporter; overdose; gamma-hydroxybutyrate
Funding
- National Institutes of Health National Institute on Drug Abuse [DA023223]
- Pfizer Global Inc
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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 1.4 +/- 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. L-lactate decreases plasma and brain ECF concentrations of GHB, decreasing sedative/hypnotic effects.
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