PT - JOURNAL ARTICLE AU - Qi Wang AU - Xiaodong Wang AU - Marilyn E. Morris TI - Effects of L-Lactate and D-Mannitol on γ-Hydroxybutyrate Toxicokinetics and Toxicodynamics in Rats AID - 10.1124/dmd.108.022996 DP - 2008 Nov 01 TA - Drug Metabolism and Disposition PG - 2244--2251 VI - 36 IP - 11 4099 - http://dmd.aspetjournals.org/content/36/11/2244.short 4100 - http://dmd.aspetjournals.org/content/36/11/2244.full SO - Drug Metab Dispos2008 Nov 01; 36 AB - 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. The American Society for Pharmacology and Experimental Therapeutics