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

γ-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.