Abstract
Overdoses of γ-hydroxybutyrate (GHB), a drug of abuse, result in coma, respiratory arrest, and death. The objective of this study was to evaluate a potential GHB detoxification strategy by inhibiting the monocarboxylate transporter (MCT)-mediated renal reabsorption of GHB in rats, using the MCT substrate l-lactate. The use of the osmotic diuretic d-mannitol alone or combined with l-lactate was also explored. GHB (208 mg/h/kg) was infused i.v. for 3 h in the absence or presence of l-lactate (60.5, 121, and 302.5 mg h-1 kg-1), d-mannitol (0.5 g/kg), or l-lactate (60.5 mg h-1 kg-1) combined with d-mannitol (0.5 g/kg). GHB in plasma and urine samples was determined along with blood pH, electrolytes, glucose, and l-lactate. Administration of l-lactate, or the combination of l-lactate and d-mannitol, but not d-mannitol alone, significantly increased the renal and total clearances of GHB in rats. Blood pH and electrolyte concentrations exhibited small changes with GHB, GHB/lactate, and GHB/mannitol treatments, although most values remained within their normal range. The concomitant administration of lactated Ringer's solution (28 mM l-lactate) at 300 μl/min with mannitol (0.5 g/kg) resulted in a significant increase in GHB clearance and a decrease in sleep time after an i.v. dose of 1 g/kg. Overall, our results indicated the following: 1) the use of the MCT inhibitor l-lactate can increase the renal and total clearances of GHB, and 2) the combination of lactated Ringer's solution and d-mannitol significantly alters GHB toxicokinetics and toxicodynamics and represents a potential clinical detoxification strategy for the treatment of GHB overdoses.
Footnotes
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This study was supported in part by the National Institutes of Health (Grant DA023223).
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doi:10.1124/dmd.108.022996.
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ABBREVIATIONS: GHB, γ-hydroxybutyrate; MCT, monocarboxylate transporter; TK, toxicokinetics; TD, toxicodynamics; LC, liquid chromatography; MS/MS, tandem mass spectrometry; GFR, glomerular filtration rate; LRR, loss of the righting reflex; RRR, regaining of the righting reflex; AUC, area under the plasma concentration-time curve; CV %, coefficient of variation; ANOVA, analysis of variance.
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↵1 Current affiliation: Bristol Myers Squibb, Pennington, New Jersey.
- Received June 19, 2008.
- Accepted August 20, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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