Feasibility of D-glucuronate to enhance gamma-hydroxybutyric acid metabolism during gamma-hydroxybutyric acid toxicity: pharmacokinetic and pharmacodynamic studies.
Gamma-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.
Bhattacharya
Indranil
I
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA.
Boje
Kathleen M K
KM
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D005965:Glucuronates / Q000494:pharmacology*; D006885:Hydroxybutyrates / Q000493:pharmacokinetics* / Q000633:toxicity*; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D005965:Glucuronates; D006885:Hydroxybutyrates; D006993:Hypnotics and Sedatives; C111420:4-hydroxybutyric acid