【原】【罂粟摘要】静脉注射s -氯胺酮对健康志愿者口服吗啡药动学的影响

静脉注射s -氯胺酮对健康志愿者口服吗啡药动学的影响

贵州医科大学           麻醉与心脏电生理课题组

翻译：田明德      编辑：田明德    审校：曹莹

背景：亚麻醉氯胺酮可减少围手术期阿片类药物的消耗。我们研究了静脉注射s -氯胺酮是否会改变健康志愿者口服吗啡的药代动力学。

方法：在这项配对、随机、双盲、交叉试验中，12名接受2小时静脉注射S-氯胺酮（0.57 mg/kg）或安慰剂输注的参与者在30分钟内接受口服吗啡（0.2 mg/kg）。24小时内对氯胺酮、吗啡及其主要代谢产物的血浆浓度进行定量。主要终点是吗啡的曲线下面积（AUC）0-24。将吗啡及其代谢物的其他药代动力学变量作为次要终点进行研究。使用Wilcoxon配对有符号秩检验（tmax）或对数变换变量（其他变量）的配对t检验，对每个参与者的数据进行阶段间比较分析。

结果：虽然两个阶段的AUC 0-24相似，但S-氯胺酮使口服吗啡的AUC 0-1.5降低了69%（与对照组的比值为0.31；90%置信区间[CI]为0.15-0.65；P=.0171），并将其tmax从0.5（范围为0.50-1.5）增加到1.0小时（范围为0.50-4.0；P=.010）。吗啡-6-葡糖苷酸（M6G）的AUC 0-1.5降低了84%（0.16；90%CI，0.07-0.37；P=0.0025），最大血浆浓度（Cmax）降低了43%（0.57；90%CCI，0.40-0.81；P=.0155），而其tmax通过S-氯胺酮从1.5（范围，1.0-2.0）增加到4.0（范围，1.0-8.0；P=.0094）小时。类似地，吗啡-3-葡糖苷酸（M3G）的AUC 0-1.5降低85%（0.15；90%CI，0.05-0.43；P=.0083），tmax从1.0（范围，0.5-1.5）增加到4.0小时（范围，1.0-8.0；P=.0063）。此外，M6G与吗啡和M3G与吗啡的代谢AUC比率在0至1.5小时内分别降低了47%（0.53；90%CI，0.39-0.71；P=.0033）和52%（0.48；90%CCI，0.27-0.85；P=.0043）。

结论：静脉注射S-氯胺酮抑制了口服吗啡的代谢并延迟了其吸收，导致前1.5小时内吗啡暴露量净减少。静脉注射S-氯胺酮可能会延迟口服止痛药和其他药物的吸收并损害其疗效。

原始文献来源： Lohela TJ, Poikola S, Backmansson D, et al. Influence of Intravenous S-Ketamine on the Pharmacokinetics of Oral Morphine in Healthy Volunteers. Anesth Analg. 2024 Mar 1;138(3):598-606. doi: 10.1213/ANE.0000000000006640. Epub 2023 Sep 21.

Influence of Intravenous S-Ketamine on the Pharmacokinetics of Oral Morphine in Healthy Volunteers

Abstract

Background: Subanesthetic ketamine may reduce perioperative consumption of opioids. We studied whether intravenous S-ketamine alters the pharmacokinetics of oral morphine in healthy volunteers.

Method: In this paired, randomized, double-blind, crossover trial, 12 participants under a 2-hour intravenous S-ketamine (0.57 mg/kg/h) or placebo infusion received oral morphine (0.2 mg/kg) at 30 minutes. Plasma concentrations of ketamine, morphine, and their major metabolites were quantified for 24 hours. The primary end point was area under the curve (AUC) 0-24 of morphine. Other pharmacokinetic variables for morphine and its metabolites were studied as secondary end points. The data were analyzed as between-phase comparisons for each participant using Wilcoxon matched-pairs signed-rank tests ( tmax ) or paired t -tests on log-transformed variables (other variables).

Results:  While the AUC 0-24 was similar between the 2 phases, S-ketamine reduced the AUC 0-1.5 of oral morphine by 69% (ratio to control, 0.31; 90% confidence interval [CI], 0.15-0.65; P = .0171) and increased its tmax from 0.5 (range, 0.50-1.5) to 1.0 hour (range, 0.50-4.0; P = .010). The AUC 0-1.5 of morphine-6-glucuronide (M6G) was reduced by 84% (0.16; 90% CI, 0.07-0.37; P = .0025) and maximum plasma concentration ( Cmax ) by 43% (0.57; 90% CI, 0.40-0.81; P = .0155), while its tmax was increased from 1.5 (range, 1.0-2.0) to 4.0 (range, 1.0-8.0; P = .0094) hours by S-ketamine. Similarly, the AUC 0-1.5 of morphine-3-glucuronide (M3G) was reduced by 85% (0.15; 90% CI, 0.05-0.43; P = .0083), and tmax increased from 1.0 (range, 0.5-1.5) to 4.0 hours (range, 1.0-8.0; P = .0063). In addition, the M6G-to-morphine and M3G-to-morphine metabolic AUC ratios were decreased by 47% (0.53; 90% CI, 0.39-0.71; P = .0033) and 52% (0.48; 90% CI, 0.27-0.85; P = .0043) during 0 to 1.5 hours and by 15% (0.85; 90% CI, 0.78-0.92; P = .0057) and 10% (0.90; 90% CI, 0.83-0.98; P = .0468) during 0 to 24 hours, respectively. One participant was excluded from the analyses due to vomiting in the S-ketamine phase.

Conclusion: Intravenous S-ketamine inhibited the metabolism of oral morphine and delayed its absorption, resulting in a net reduction in the exposure to morphine during the first 1.5 hours. Intravenous S-ketamine may delay the absorption and impair the efficacy of orally administered analgesics and other drugs.