Feasibility of D-glucuronate to enhance γ-hydroxybutyric acid metabolism during γ-hydroxybutyric acid toxicity: pharmacokinetic and pharmacodynamic studies

✍ Scribed by Indranil Bhattacharya; Kathleen M. K. Boje

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 162 KB
• Volume: 28
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.525

✦ Synopsis

g-Hydroxybutyric acid (GHB) is a drug of abuse. Literature studies showed that d-glucuronate acts as an oxidative stimulator of GHB metabolism following in vivo GHB tracer doses. The present proof-of-concept study investigates if d-glucuronate enhances GHB metabolism and inhibits blood-brain barrier (BBB) carrier-mediated transport of GHB for clinically relevant and toxicological concentrations of GHB. In a randomized cross-over study with a 3 day washout period, rats were intravenously administered GHB (200, 400 or 800 mg/kg) with either saline or d-glucuronate (830 mg/kg i.v. bolus followed by a constant infusion of 1.39 g/kg-h). Systemic and renal GHB pharmacokinetics, as well as onset, offset and duration of GHB sedative/hypnotic effects were measured following each GHB dose. In situ brain perfusion was used to determine if d-glucuronate inhibited GHB BBB transport. d-Glucuronate did not alter GHB sedative/hypnotic effects at all three GHB doses. A model independent approach revealed that GHB systemic (AUC, CL Total , CL Metabolism , V SS , T 1/2 ) and renal (CL Renal , f e ) pharmacokinetic parameters were unaltered by d-glucuronate administration. GHB influx clearance was unaltered by d-glucuronate suggesting a lack of transport inhibition. These observations suggest that although previously shown to be promising at GHB tracer doses, d-glucuronate lacks therapeutic benefit in the treatment of GHB toxicity.