Toxicokinetics/Toxicodynamics of γ-Hydroxybutyrate-Ethanol Intoxication: Evaluation of Potential Treatment Strategies
Toxicokinetics/Toxicodynamics of γ-Hydroxybutyrate-Ethanol Intoxication: Evaluation of Potential Treatment Strategies
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DOI：
10.1124/jpet.113.206250
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发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Morris, Marilyn E.
中科院分区：
文献类型：
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作者：
Morse, Bridget L.;Morris, Marilyn E.
伽马-羟丁酸酯(GHB)是一种常见的滥用药物，通常与乙醇包裹在一起。通过抑制单羧酸转运体(MCT)增加肾脏清除量是GHB过量的一种潜在治疗策略，抑制GABA(B)受体也是如此。在这项研究中，我们研究了GHB-乙醇之间的毒代动力学/毒理动力学相互作用和GHB-乙醇中毒的治疗方案的疗效。镇静程度以恢复正位反射为终点进行评估。呼吸采用体积描记术进行评估。联用2.0g/kg乙醇静脉注射。静脉注射600 mg/kg GHB。与单独服用GHB相比，睡眠时间增加。给药至稳态浓度为0.1-0.2%和0.3-0.4%(w/v)的乙醇不影响600 mg/kg GHB的毒代动力学或呼吸频率，但与单独使用GHB相比，峰值潮气量显著降低。口服2.5g/kg乙醇对口服1500 mg/kg GHB的毒代动力学无明显影响。GABA(A)受体抑制对GHB乙醇中毒大鼠的睡眠时间和呼吸抑制无明显影响。GABA(B)受体抑制可部分阻止镇静，并完全阻止呼吸抑制。与1500 mg/kg GHB静脉注射相比，注射0.1-0.2%(4/10)和0.3-0.4%(9/10)的乙醇会增加死亡率。单独(10分中的0分)。使用MCT抑制剂L-乳酸治疗，显著减少了GHB-乙醇后的睡眠时间，并降低了0.1-0.2%(0/10)和0.3-0.4%(5/10)的死亡率。用GABAB受体拮抗剂治疗完全避免了0.3-0.4%(0/10)的死亡率。这些数据表明，乙醇增强了GHB的镇静和呼吸抑制作用，增加了死亡的风险。MCT和GABA(B)受体抑制是治疗GHB-乙醇中毒的潜在有效方法。
gamma-Hydroxybutyrate (GHB), a common drug of abuse, is often coingested with ethanol. Increasing renal clearance via monocarboxylate transporter (MCT) inhibition represents a potential therapeutic strategy in GHB overdose, as does inhibition of GABA(B) receptors. In this study, we investigate toxicokinetic/toxicodynamic interactions between GHB-ethanol and efficacy of treatment options for GHB-ethanol intoxication in rats. Sedation was assessed using the endpoint of return-to-righting reflex. Respiration was assessed using plethysmography. Coadministration of 2.0 g/kg ethanol i.v. with 600 mg/kg GHB i.v. increased sleep time compared with GHB alone. Administration of ethanol to steady-state concentrations of 0.1-0.2% and 0.3-0.4% (w/v) did not affect toxicokinetics of 600 mg/kg GHB i.v., or respiratory rate, but did result in significantly lower peak tidal volumes compared with GHB alone. Oral administration of 2.5 g/kg ethanol had no significant effect on toxicokinetics of 1500 mg/kg orally administered GHB. Pretreatment with specific receptor inhibitors indicated no effect of GABA(A) receptor inhibition on sleep time or respiratory depression in GHB-ethanol intoxication. GABA(B) receptor inhibition partially prevented sedation and completely prevented respiratory depression. Ethanol increased fatality when administered at 0.1-0.2% (4 of 10) and 0.3-0.4% (9 of 10) versus 1500 mg/kg GHB i.v. alone (0 of 10). Treatment with the MCT inhibitor, L-lactate, significantly decreased sleep time after GHB-ethanol and decreased fatality at 0.1-0.2% (0 of 10) and 0.3-0.4% ethanol (5 of 10). Treatment with a GABAB receptor antagonist completely prevented fatality at 0.3-0.4% (0 of 10). These data indicate that ethanol potentiates the sedative and respiratory depressant effects of GHB, increasing the risk of fatality. MCT and GABA(B) receptor inhibition represent potentially effective treatments in GHB-ethanol intoxication.