Effects of L-lactate and D-mannitol on gamma-hydroxybutyrate toxicokinetics and toxicodynamics in rats.
Overdoses of gamma-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 mul/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.
Wang
Qi
Q
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260, USA.
Wang
Xiaodong
X
Morris
Marilyn E
ME
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008658:Inactivation, Metabolic; D019344:Lactic Acid / Q000008:administration & dosage*; D008297:Male; D008353:Mannitol / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012978:Sodium Oxybate / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D013237:Stereoisomerism
D004338:Drug Combinations; D019344:Lactic Acid; D008353:Mannitol; D012978:Sodium Oxybate