一种新型单羧酸转运体抑制剂作为γ-羟基丁酸过量的潜在治疗策略。
A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose.
作者信息
Vijay Nisha, Morse Bridget L, Morris Marilyn E
机构信息
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, New York, 14214-8033, USA.
出版信息
Pharm Res. 2015 Jun;32(6):1894-906. doi: 10.1007/s11095-014-1583-0. Epub 2014 Dec 6.
PURPOSE
Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for γ-hydroxybutyric acid (GHB) overdose by blocking its renal reabsorption in the kidney. This study further evaluated the effects of a novel, highly potent MCT inhibitor, AR-C155858, on GHB toxicokinetics/toxicodynamics (TK/TD).
METHODS
Rats were administered GHB (200, 600 or 1500 mg/kg i.v. or 1500 mg/kg po) with and without AR-C155858. Breathing frequency was continuously monitored using whole-body plethysmography. Plasma and urine samples were collected up to 8 h. The effect of AR-C155858 on GHB brain/plasma partitioning was also assessed.
RESULTS
AR-C155858 treatment significantly increased GHB renal and total clearance after intravenous GHB administration at all the GHB doses used in this study. GHB-induced respiratory depression was significantly improved by AR-C155858 as demonstrated by an improvement in the respiratory rate. AR-C155858 treatment also resulted in a significant reduction in brain/plasma partitioning of GHB (0.1 ± 0.03) when compared to GHB alone (0.25 ± 0.02). GHB CLR and CLoral (CL/F) following oral administration were also significantly increased following AR-C155858 treatment (from 1.82 ± 0.63 to 5.74 ± 0.86 and 6.52 ± 0.88 to 10.2 ± 0.75 ml/min/kg, respectively).
CONCLUSION
The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.
目的
单羧酸转运体（MCT）抑制是一种潜在的治疗策略，可通过阻断γ-羟基丁酸（GHB）在肾脏的重吸收来治疗GHB过量中毒。本研究进一步评估了新型高效MCT抑制剂AR-C155858对GHB毒代动力学/毒效动力学（TK/TD）的影响。
方法
给大鼠静脉注射或口服GHB（200、600或1500mg/kg），同时给予或不给予AR-C155858。使用全身体积描记法连续监测呼吸频率。采集血浆和尿液样本长达8小时。还评估了AR-C155858对GHB脑/血浆分配的影响。
结果
在本研究使用的所有GHB剂量下，静脉注射GHB后，AR-C155858治疗显著增加了GHB的肾脏清除率和总清除率。AR-C155858显著改善了GHB诱导的呼吸抑制，表现为呼吸频率的改善。与单独使用GHB相比（0.25±0.02），AR-C155858治疗还导致GHB的脑/血浆分配显著降低（0.1±0.03）。口服给药后，AR-C155858治疗后GHB的肾清除率（CLR）和口服清除率（CL/F）也显著增加（分别从1.82±0.63增至5.74±0.86以及从6.52±0.88增至10.2±0.75ml/min/kg）。
结论
这种新型高效的MCT抑制剂是治疗GHB过量中毒的一种潜在选择。
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