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

作者：Vijay Nisha; Morse Bridget L; Morris Marilyn E^*

来源：Pharmaceutical Research, 2015, 32(6): 1894-1906.

DOI：10.1007/s11095-014-1583-0

• AR-C155858
• GHB
• MCT inhibitor
• respiratory depression
• toxicity

Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for gamma-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).
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.
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).
The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.

• 出版日期2015-6