Kwatra Nisha V, Morris Marilyn E
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, Buffalo, NY 14214, USA.
Division of Inflammation and Immune Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Pharmaceutics. 2021 May 18;13(5):741. doi: 10.3390/pharmaceutics13050741.
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 (GABA 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 GABA receptor antagonism can serve as potential treatment strategies for GHB overdose when it is co-ingested with ketamine.
γ-羟基丁酸（GHB）被广泛单独滥用，或与氯胺酮等其他俱乐部药物联合滥用。GHB呈现非线性毒代动力学，其特征为通过单羧酸转运体（MCTs）介导的可饱和代谢、可饱和吸收和可饱和肾重吸收。在本研究中，我们描述了氯胺酮对GHB毒代动力学/毒效动力学（TK/TD）的影响，并评估了在氯胺酮存在的情况下，使用MCT抑制和特异性受体拮抗作为GHB过量潜在治疗策略的效果。成年雄性Sprague-Dawley大鼠静脉注射600 mg/kg GHB，单独给药或与氯胺酮（静脉推注6 mg/kg加静脉输注1 mg/kg/分钟）联合给药。采集血浆和尿液样本，并使用全身体积描记法连续监测呼吸参数（呼吸频率、潮气量和分钟通气量）。联合使用氯胺酮导致GHB的总清除率和代谢清除率显著降低，而肾清除率保持不变。氯胺酮阻止了GHB引起的潮气量代偿性增加，与单独使用GHB相比，这导致分钟通气量显著下降。与单独使用GHB相比，联合使用氯胺酮后睡眠时间和致死率也有所增加。L-乳酸和AR-C155858（强效MCT抑制剂）治疗导致GHB的肾清除率和总清除率增加，并改善了呼吸抑制。给予AR-C155858还导致GHB脑/血浆比值显著降低。SCH50911（GABA受体拮抗剂）而非纳洛酮改善了氯胺酮存在时GHB引起的呼吸抑制。总之，同时摄入氯胺酮和GHB可导致显著的TK/TD相互作用。当GHB与氯胺酮同时摄入时，MCT抑制和GABA受体拮抗可作为GHB过量的潜在治疗策略。
