Renal clearance of gamma-hydroxybutyric acid in rats: increasing renal elimination as a detoxification strategy.
Intoxication with gamma-hydroxybutyric acid (GHB) is associated with coma, seizure, and death; treatment of overdoses is symptomatic. The objectives of this investigation were to characterize the renal clearance and total clearance of GHB in rats and to evaluate potential strategies for increasing the elimination of GHB after drug overdoses. GHB was administered by i.v. infusion at low (108 mg/h/kg), medium (128 mg/h/kg), or high (208 mg/h/kg) doses. Crossover studies were performed under steady-state conditions using the medium dose in the absence or presence of l-lactate, pyruvate, d-mannitol, sodium bicarbonate, or normal saline. GHB in plasma and urine samples was assayed using liquid chromatography-tandem mass spectrometry. Infusion of the low, medium, and high doses of GHB produced steady-state plasma concentrations of 0.22 +/- 0.04, 0.43 +/- 0.05, and 0.68 +/- 0.11 mg/ml. The renal clearance of the medium (51.8 +/- 13.0 ml/h/kg) and high (97.1 +/- 43.1 ml/h/kg) doses was significantly higher than that of the low dose (14.9 +/- 5.1 ml/h/kg), whereas the total clearance values were significantly lower than that of the low dose. The renal clearance was significantly increased by the concomitant administration of l-lactate, pyruvate, d-mannitol, or sodium bicarbonate with GHB but was not altered by normal saline. The total and metabolic clearance values were significantly increased by all treatments except normal saline. Overall, our results indicated that the renal clearance of GHB is dose-dependent, involving capacity-limited reabsorption. Monocarboxylate transport inhibitors, osmotic diuresis using d-mannitol, or the administration of sodium bicarbonate can increase the renal and total clearances of GHB. The approaches used in this investigation may offer potential detoxification strategies for the treatment of GHB overdoses.
Morris
Marilyn E
ME
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, 14260, USA. memorris@buffalo.edu
Hu
Ke
K
Wang
Qi
Q
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D006885:Hydroxybutyrates / Q000493:pharmacokinetics*; D008658:Inactivation, Metabolic; D007668:Kidney / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D006885:Hydroxybutyrates; C111420:4-hydroxybutyric acid