Abstract
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.
Highlights
IntroductionWe characterized the effects of ketamine on GHB toxicokinetics/toxicodynamics (TK/TD) and evaluated the use of monocarboxylate transporters (MCTs) inhibition and specific receptor antagonism as potential treatment strategies for GHB overdose in the presence of ketamine
To further investigate the involvement of protein kinase C (PKC) in the increase in GHB uptake observed in the presinvestigate the involvement of PKC in the increase in GHB uptake observed in the presence ence of ketamine, we further studied the effect of phorbol 12-myristate 13-acetate (PMA) and ketamine on GHB uptake in of ketamine, we further studied the effect of PMA and ketamine on GHB uptake in the presthe presence and absence of a nonspecific PKC inhibitor, staurosporine (Figure 7)
Our toxicokinetic studies indicate that plasma exposure of GHB is significantly increased in the presence of ketamine when compared to GHB alone and metabolic and total clearance is significantly decreased while renal clearance remains unchanged
Summary
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. L-lactate and AR-C155858 (potent MCT inhibitor) treatment resulted in an increase in GHB renal and total clearance and improvement in respiratory depression. 1. Introduction γ-hydroxybutyric acid (GHB, with the street name of Liquid Ecstasy) is a recreational drug that is widely abused for its euphotic effects at nightclubs and raves. Introduction γ-hydroxybutyric acid (GHB, with the street name of Liquid Ecstasy) is a recreational drug that is widely abused for its euphotic effects at nightclubs and raves It was reported in 2011 by Substance Abuse and Mental Health Services Administration that emergency department visits resulting from GHB overdose in the United States range between.
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