TY - JOUR T1 - <strong>γ</strong><strong>-Hydroxybutyric Acid-Ethanol Drug-Drug Interaction: Reversal of toxicity with MCT1 inhibitors</strong> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000566 SP - JPET-AR-2021-000566 AU - Vivian Rodriguez-Cruz AU - Marilyn E. Morris Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/06/15/jpet.121.000566.abstract N2 - The drug of abuse, γ-hydroxybutyric acid (GHB), is commonly co-ingested with ethanol, resulting in a high incidence of toxicity and death. Our laboratory has previously reported that GHB is a substrate for the monocarboxylate transporters (MCT), necessary for its absorption, renal clearance, and tissue distribution, including across the blood-brain barrier. Our goal was to investigate the drug-drug interaction (DDI) between GHB-ethanol and evaluate MCT1 inhibition as a strategy to reverse toxicity. The toxicokinetics of this DDI were investigated, including brain to plasma concentration ratios, in the presence and absence of ethanol. The toxicodynamic parameters examined were respiratory depression (breathing frequency, tidal volume) and sedation (time of return-of-righting reflex). Ethanol was administered (2 g/kg i.v.) 5 min before the i.v. or oral administration of GHB, and MCT1 inhibitors, AZD-3965 and AR-C155858 (5mg/kg i.v.) were administered 60 min after GHB administration. Ethanol administration did not alter the toxicokinetics or respiratory depression caused by GHB after i.v. or oral administration; however, it significantly increased the sedation effect, measured by return-to-righting time. AZD-3965 or AR-C155858 significantly decreased the effects of the co-administration of GHB and ethanol on respiratory depression and sedation of this DDI, and decreased brain concentrations and the brain/plasma concentration ratio of GHB. The results indicate that ethanol co-administered with GHB increases toxicity and MCT1 inhibition is effective in reversing toxicity by inhibiting GHB brain uptake when given post-GHB/ethanol administration. Significance Statement The aim of this project was to investigate the enhanced toxicity observed clinically when GHB is co-ingested the alcohol, and evaluate strategies to reverse this toxicity. The effects of the novel MCT1 inhibitors AR-C155858 and AZD-3965 on this drug-drug interaction have not been studied before, and our preclinical studies indicate that MCT1 inhibitors can decrease brain concentrations of GHB by inhibiting brain uptake, even when administered at times after GHB/ethanol. AZD-3965 represents a potential treatment strategy for GHB/ethanol overdoses. ER -