Toxicokinetic/Toxicodynamic Interaction Studies in Rats between the Drugs of Abuse γ-Hydroxybutyric Acid and Ketamine and Treatment Strategies for Overdose.
Toxicokinetic/Toxicodynamic Interaction Studies in Rats between the Drugs of Abuse γ-Hydroxybutyric Acid and Ketamine and Treatment Strategies for Overdose.
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DOI：
10.3390/pharmaceutics13050741
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发表时间：
2021-05-18
期刊：
影响因子：
5.4
通讯作者：
Morris ME
中科院分区：
文献类型：
--
作者：
Kwatra NV;Morris ME
γ-羟基丁酸（GHB）被广泛单独滥用，并与其他俱乐部药物如氯胺酮一起滥用。GHB具有非线性毒代动力学，其特征在于单羧酸转运蛋白（MCT）介导的饱和代谢、饱和吸收和饱和肾重吸收。在本研究中，我们表征了氯胺酮对GHB毒代动力学/毒代动力学（TK/TD）的影响，并评估了在氯胺酮存在下使用MCT抑制和特异性受体拮抗作用作为GHB过量的潜在治疗策略。对成年雄性Sprague-Dawley大鼠单独或与氯胺酮（6 mg/kg静脉推注加1 mg/kg/min静脉输注）一起静脉给予600 mg/kg GHB。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）。氯胺酮联合给药导致GHB总清除率和代谢清除率显著降低，肾脏清除率保持不变。氯胺酮阻止了GHB产生的潮气量的代偿性增加，与单独使用GHB相比，这导致分钟通气量显著下降。与GHB相比，氯胺酮联合给药后睡眠时间和致死率也增加。L-乳酸盐和AR-C155858（强效MCT抑制剂）治疗导致GHB肾脏和总清除率增加，呼吸抑制改善。AR-C155858给药还导致GHB脑/血浆比值显著降低。SCH 50911（GABAB受体拮抗剂），而不是纳洛酮，改善GHB诱导的呼吸抑制氯胺酮的存在。总之，氯胺酮与GHB一起摄入可导致显著的TK/TD相互作用。MCT抑制和GABAB受体拮抗作用可作为GHB与氯胺酮联合摄入过量的潜在治疗策略。
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 (GABAB 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 GABAB receptor antagonism can serve as potential treatment strategies for GHB overdose when it is co-ingested with ketamine.
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10.1152/ajpendo.1997.273.1.e207
发表时间：
1997-07-01
影响因子：
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作者：
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影响因子：
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影响因子：
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影响因子：
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发表时间：
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影响因子：
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