PT  - JOURNAL ARTICLE
AU  - Kristin E Follman
AU  - Marilyn E Morris
TI  - Treatment of γ-Hydroxybutyric Acid (GHB) and γ-Butyrolactone (GBL) Overdose with Two Potent Monocarboxylate Transporter 1 (MCT1) Inhibitors, AZD3965 and AR-C155858
AID  - 10.1124/jpet.119.256503
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.256503
4099  - http://jpet.aspetjournals.org/content/early/2019/04/22/jpet.119.256503.short
4100  - http://jpet.aspetjournals.org/content/early/2019/04/22/jpet.119.256503.full
AB  - The illicit use of γ-hydroxybutyric acid (GHB), and its prodrug, γ-butyrolactone (GBL), results in severe adverse effects including sedation, coma, respiratory depression and death. Current treatment of GHB/GBL overdose is limited to supportive care. Recent reports indicate that GHB-related deaths are on the rise; a specific treatment may reduce lethality associated with GHB/GBL. Pretreatment with inhibitors of monocarboxylate transporter 1 (MCT1), a transporter which mediates many of processes involved in the absorption, distribution (including brain uptake) and elimination of GHB/GBL, has been shown to prevent GHB induced respiratory depression by increasing the CLR of GHB. In order to identify whether MCT1 inhibition is an effective treatment for GHB overdose, the impact of two MCT1 inhibitors, AZD3965 and AR-C155858, on the toxicokinetics and toxicodynamics of GHB/GBL were assessed when the administration of the inhibitor was delayed 60 and 120 minutes (post-treatment) after administration of GHB/GBL. AR-C155858 and AZD3965 reduced the toxicodynamic effects of GHB when GHB was administered intravenously, orally or orally as the pro-drug GBL. The impact of these inhibitors on GHB toxicokinetics was dependent on route of GHB administration and the delay between GHB/GBL administration and administration of the MCT1 inhibitor. The reduction in GHB plasma exposure did not explain the observed effect of MCT1 inhibition on GHB-induced respiratory depression. The efficacy of MCT1 inhibition on GHB toxicodynamics is likely driven by the pronounced reduction in GHB brain concentrations. Overall, this study indicates that inhibition of MCT1 is an effective treatment for GHB/GBL overdose.SIGNIFICANCE STATEMENT This research demonstrates the efficacy of a potent MCT1 inhibitor, AZD2965, as a treatment for GHB overdose. AZD3965 was shown to reduce the brain exposure of GHB, and therefore reduce the toxic impact of GHB. This compound may have the potential to be developed to treat GHB overdose clinically.