基于模型的分析：氯胺酮及其主要代谢物去甲氯胺酮、羟基去甲氯胺酮和去氢去甲氯胺酮的药代动力学。
Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis.
机构信息
Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
出版信息
Br J Anaesth. 2020 Nov;125(5):750-761. doi: 10.1016/j.bja.2020.06.067. Epub 2020 Aug 21.
BACKGROUND
Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers.
METHODS
Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach.
RESULTS
The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics.
CONCLUSIONS
The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites.
CLINICAL TRIAL REGISTRATION
Dutch Cochrane Center 5359.
背景
最近的研究表明，氯胺酮代谢物，如羟基去甲氯胺酮，具有缓解抑郁相关症状和镇痛的作用。为了更好地了解氯胺酮及其代谢物去甲氯胺酮、脱水去甲氯胺酮和羟基去甲氯胺酮的药代动力学，我们建立了氯胺酮及其 S-对映体（艾司氯胺酮）静脉给药后药代动力学的群体药代动力学模型。药代动力学数据来自于一项关于硝普钠（SNP）降低氯胺酮在人类志愿者中致幻副作用的疗效的随机对照试验。
方法
将三种递增的艾司氯胺酮和外消旋氯胺酮静脉剂量给予 20 名健康志愿者，并采集动脉血浆样本以测量氯胺酮和代谢物。受试者被随机分为四组，分别接受艾司氯胺酮/SNP、艾司氯胺酮/安慰剂、外消旋氯胺酮/SNP 和外消旋氯胺酮/安慰剂。采用群体房室模型分析方法对氯胺酮和代谢物的时间-血浆浓度数据进行分析。
结果
氯胺酮和代谢物的药代动力学用一个七房室模型来描述，该模型有两个氯胺酮、去甲氯胺酮和羟基去甲氯胺酮室，以及一个脱水去甲氯胺酮室，代谢室位于氯胺酮和去甲氯胺酮之间，去甲氯胺酮和脱水去甲氯胺酮主要室之间。S-和 R-氯胺酮对映体的药代动力学有显著差异，无论剂型如何，R-对映体的清除率都低了 50%。虽然 SNP 对氯胺酮的清除率有显著影响，但模拟结果表明 SNP 对总氯胺酮的药代动力学影响较小。
结论
该模型质量良好，可用于未来研究氯胺酮及其代谢物的疗效和副作用的药代动力学和药效动力学。
临床试验注册号
荷兰 Cochrane 中心 5359。
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