| Feasibility of D-glucuronate to enhance gamma-hydroxybutyric acid metabolism during gamma-hydroxybutyric acid toxicity: pharmacokinetic and pharmacodynamic studies. | |
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MedLine Citation:
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PMID: 17061294 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Indranil Bhattacharya; Kathleen M K Boje |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biopharmaceutics & drug disposition Volume: 28 ISSN: 0142-2782 ISO Abbreviation: Biopharm Drug Dispos Publication Date: 2007 Jan |
Date Detail:
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Created Date: 2006-12-25 Completed Date: 2007-03-21 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 7911226 Medline TA: Biopharm Drug Dispos Country: England |
Other Details:
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Languages: eng Pagination: 1-11 Citation Subset: IM |
Copyright Information:
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Copyright 2006 John Wiley & Sons, Ltd. |
Affiliation:
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Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood-Brain Barrier / drug effects, metabolism Glucuronates / pharmacology* Hydroxybutyrates / pharmacokinetics*, toxicity* Hypnotics and Sedatives / pharmacokinetics*, toxicity* Kidney / drug effects, metabolism Male Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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DA 14988/DA/NIDA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Glucuronates; 0/Hydroxybutyrates; 0/Hypnotics and Sedatives; 591-81-1/4-hydroxybutyric acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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