title: A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose.
abstract: OBJECTIVE
  Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for γ-hydroxybutyric acid (GHB) overdose by blocking its renal reabsorption in the kidney. This study further evaluated the effects of a novel, highly potent MCT inhibitor, AR-C155858, on GHB toxicokinetics/toxicodynamics (TK/TD).
  
  
  METHODS
  Rats were administered GHB (200, 600 or 1500 mg/kg i.v. or 1500 mg/kg po) with and without AR-C155858. Breathing frequency was continuously monitored using whole-body plethysmography. Plasma and urine samples were collected up to 8 h. The effect of AR-C155858 on GHB brain/plasma partitioning was also assessed.
  
  
  RESULTS
  AR-C155858 treatment significantly increased GHB renal and total clearance after intravenous GHB administration at all the GHB doses used in this study. GHB-induced respiratory depression was significantly improved by AR-C155858 as demonstrated by an improvement in the respiratory rate. AR-C155858 treatment also resulted in a significant reduction in brain/plasma partitioning of GHB (0.1 ± 0.03) when compared to GHB alone (0.25 ± 0.02). GHB CLR and CLoral (CL/F) following oral administration were also significantly increased following AR-C155858 treatment (from 1.82 ± 0.63 to 5.74 ± 0.86 and 6.52 ± 0.88 to 10.2 ± 0.75 ml/min/kg, respectively).
  
  
  CONCLUSIONS
  The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, New York, 14214-8033, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Vijay
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Morse
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D062787:Drug Overdose / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D065608:Renal Reabsorption / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D056152:Respiratory Rate / Q000187:drug effects; D012978:Sodium Oxybate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013876:Thiophenes / Q000494:pharmacology*; D014018:Tissue Distribution; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C546977:AR C155858; D000931:Antidotes; D027501:Monocarboxylic Acid Transporters; D013876:Thiophenes; D014498:Uracil; D012978:Sodium Oxybate