Gamma-Hydroxybutyrate Toxicokinetics and Toxicodynamics Are Influenced by Sex and Cross-Sex Estrogen/Progesterone Treatment

Background/Objectives: Non-medical use of GHB poses a public health risk due to the risk of overdose. GHB exhibits nonlinear toxicokinetics mediated by monocarboxylate transporters (MCTs), and previous studies have demonstrated sex-related differences in transporter regulation and GHB toxicokinetics. This study investigated the impact of exogenous estrogen and progesterone on GHB toxicokinetics and toxicodynamics, and evaluated the efficacy of AR-C155858 (an MCT1 inhibitor) to treat GHB overdose. Methods: Ovariectomized (OVX) females and castrated (CST) male Sprague Dawley rats were treated with estrogen and/or progesterone or a corresponding placebo for 21 days. Rats received intravenous GHB (1000 or 1500 mg/kg) or GHB + AR-C155858 (1500 mg/kg + 1 mg/kg), and plasma and urine samples were collected for 8 h post-dose. GHB concentrations were quantified by a validated LC/MS assay. Results: Female sex hormones significantly affected GHB toxicokinetics. Treatment with estrogen and progesterone (alone or in combination) reduced GHB exposure in OVX and CST rats through altered GHB clearance. Alterations in renal and metabolic clearance were dose-dependent. GHB exposure was significantly decreased with the co-administration of AR-C155858, as a result of increased GHB renal clearance. Conclusions: Female sex hormones influence GHB toxicokinetics, with combined estrogen/progesterone treatment producing the greatest reductions in systemic GHB exposure and toxicity. Monocarboxylate transporter inhibition with AR-C155858 significantly decreased GHB exposure and sedative effect, supporting its potential as a therapeutic strategy for GHB overdose across diverse populations.