A novel monocarboxylate transporter inhibitor as a potential treatment strategy for γ-hydroxybutyric acid overdose

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. ARC-155858 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 CL_R and CL_oral (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.