γ-hydroxybutyric
acid (GHB) is widely abused alone and in combination with other
club drugs such as
ketamine. GHB exhibits nonlinear toxicokinetics, characterized by saturable metabolism, saturable absorption and saturable renal reabsorption mediated by monocarboxylate transporters (MCTs). In this research, we characterized the effects of
ketamine on GHB toxicokinetics/toxicodynamics (TK/TD) and evaluated the use of MCT inhibition and specific receptor antagonism as potential treatment strategies for GHB overdose in the presence of
ketamine. Adult male Sprague-Dawley rats were administered GHB 600 mg/kg i.v. alone or with
ketamine (6 mg/kg i.v. bolus plus 1 mg/kg/min i.v. infusion). Plasma and urine samples were collected and respiratory parameters (breathing frequency, tidal and minute volume) continuously monitored using whole-body plethysmography.
Ketamine co-administration resulted in a significant decrease in GHB total and metabolic clearance, with renal clearance remaining unchanged.
Ketamine prevented the compensatory increase in tidal volume produced by GHB, and this resulted in a significant decline in minute volume when compared to GHB alone. Sleep time and lethality were also increased after
ketamine co-administration when compared to GHB. L-
lactate and
AR-C155858 (potent MCT inhibitor) treatment resulted in an increase in GHB renal and total clearance and improvement in
respiratory depression.
AR-C155858 administration also resulted in a significant decrease in GHB brain/plasma ratio. SCH50911 (GABAB receptor antagonist), but not
naloxone, improved GHB-induced
respiratory depression in the presence of
ketamine. In conclusion,
ketamine ingestion with GHB can result in significant TK/TD interactions. MCT inhibition and GABAB receptor antagonism can serve as potential treatment strategies for GHB overdose when it is co-ingested with
ketamine.