Fox A W, Sullivan B W, Buffini J D, Neichin M L, Nicora R, Hoehler F K, O'Rourke R, Stoltz R R
Drug Development Division, Cypros Pharmaceutical Corporation, Carlsbad, California, USA.
J Pharmacol Exp Ther. 1996 Nov;279(2):686-93.
Sodium dichloroacetate (DCA) or placebo, two infusions 30 min in duration and 8 h apart, was administered to healthy subjects under double-blind conditions. The objectives were to characterize accurately the tolerability of DCA, its pharmacokinetics, and the reduction of resting serum lactate concentration by DCA. A hybrid, one-compartment pharmacokinetic model fitted best, with zero-order elimination mean of 27.9 micrograms/ml/h at concentrations above about 80 to 120 micrograms/ml, and with first-order elimination (mean kelim = 0.54) at lower serum concentrations of DCA. Resting serum lactate was dose-independently, maximally reduced within 15 min of the end of all active infusions. The duration of suppression of resting serum lactate was dose-dependent, from 4.5 h (30 mg/kg) to > 8 h (100 mg/kg). Second infusions (15-50 mg/kg) again promptly and maximally reduced resting serum lactate. Hysteresis loops were asymmetrical for all doses but exhibited change in shape that was dose-dependent; no good pharmacokinetic-pharmacodynamic model could be fitted that was consistent between doses. Infusions were well tolerated, 100 mg/kg + 50 mg/kg being the highest doses. Somnolence, the only dose-related adverse event, was reported by 3 of 37 subjects at times corresponding to the highest serum DCA concentrations. This study demonstrates the tolerability of i.v. DCA, proposes a simple pharmacokinetic model for its elimination, characterizes the dose-response relationship in terms of time course of effect, shows the dissociation between elimination of DCA and offset of response and will guide further studies of DCA in patients with head injury or stroke.
在双盲条件下，向健康受试者输注二氯醋酸钠（DCA）或安慰剂，每次输注持续30分钟，间隔8小时。目的是准确描述DCA的耐受性、药代动力学以及DCA对静息血清乳酸浓度的降低作用。一个混合的一室药代动力学模型拟合效果最佳，在浓度高于约80至120微克/毫升时，零级消除均值为27.9微克/毫升/小时，而在较低血清DCA浓度下为一级消除（平均消除速率常数kelim = 0.54）。静息血清乳酸在所有活性输注结束后15分钟内呈剂量依赖性最大程度降低。静息血清乳酸抑制持续时间呈剂量依赖性，从4.5小时（30毫克/千克）到>8小时（100毫克/千克）。第二次输注（15 - 50毫克/千克）再次迅速且最大程度地降低了静息血清乳酸。所有剂量的滞后环均不对称，但形状变化呈剂量依赖性；无法拟合出在不同剂量间一致的良好药代动力学 - 药效学模型。输注耐受性良好，100毫克/千克 + 50毫克/千克为最高剂量。嗜睡是唯一与剂量相关的不良事件，37名受试者中有3名在血清DCA浓度最高时报告出现嗜睡。本研究证明了静脉注射DCA的耐受性，提出了其消除的简单药代动力学模型，描述了效应时间过程方面的剂量 - 反应关系，显示了DCA消除与反应消退之间的分离，并将指导对颅脑损伤或中风患者进行DCA的进一步研究。
