A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose.

Abstract

PURPOSE:

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).

CONCLUSION:

The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.

• Authors: Nisha Vijay, Bridget L Morse, Marilyn E Morris
• Journal: Pharmaceutical research (Pharm Res) Vol. 32 Issue 6 Pg. 1894-906 (Jun 2015) ISSN: 1573-904X [Electronic] United States
• PMID: 25480120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• AR C155858
• Antidotes
• Monocarboxylic Acid Transporters
• Thiophenes
• Uracil
• Sodium Oxybate

Topics

• Administration, Intravenous
• Administration, Oral
• Animals
• Antidotes (pharmacology)
• Brain (metabolism)
• Cell Line
• Drug Overdose (drug therapy, metabolism)
• Kidney (drug effects, metabolism)
• Male
• Metabolic Clearance Rate
• Monocarboxylic Acid Transporters (antagonists & inhibitors, metabolism)
• Rats, Sprague-Dawley
• Renal Reabsorption (drug effects)
• Respiratory Insufficiency (chemically induced, drug therapy, metabolism, physiopathology)
• Respiratory Rate (drug effects)
• Sodium Oxybate (administration & dosage, pharmacokinetics, toxicity)
• Thiophenes (pharmacology)
• Tissue Distribution
• Uracil (analogs & derivatives, pharmacology)