罂粟摘要 利福平可降低健康志愿者经口服或静脉注射氢吗啡酮的血浆浓度
利福平可降低健康志愿者经口服或静脉注射氢吗啡酮
的血浆浓度
贵州医科大学 麻醉与心脏电生理课题组
翻译：潘志军 编辑：马艳燕 审校：曹莹
一些阿片类药物是由诱导型细胞色素P450（CYP）3A同工酶代谢的。当与药物代谢的强诱导剂(如利福平)合用时，可显著减少这些阿片类药物在机体的作用。由于氢吗啡酮的CYP代谢并不重要，所以我们在健康志愿者中研究了氢吗啡酮是否能对同时接受典型药酶诱导剂利福平的患者产生同样有效的镇痛效果。
在这项配对、随机、交叉研究中，12名参与者被分为为期8天的口服安慰剂（组）或利福平（组）。在第6天口服氢吗啡酮(2.6mg)，第8天静脉注射氢吗啡酮(0.02mg/kg)。测量氢吗啡酮和氢吗啡酮-3-葡萄糖醛酸苷(HM3G)24小时的血浆浓度，并评估6小时的精神运动反应，包括感知的药物效应、瞳孔直径变化和冷加压试验阈值。我们的主要结局指标是利福平或安慰剂预处理后口服和静脉注射氢吗啡酮的浓度-时间曲线下面积的变化。药效学参数和其他药代动力学参数作为次要结局指标进行分析。
利福平将口服和静脉注射氢吗啡酮的浓度-时间曲线下面积分别降低了 43% （与对照组的比率：0.57，90%置信区间[CI]，0.50-0.65）和26%（与对照组的比率：0.74，90% CI，0.69-0.79）。与安慰剂相比，利福平作用下口服氢吗啡酮的最大药物浓度降低37%（与对照组的比率：0.63，90% CI，0.55-0.72），口服药效率从33%降至26%（与对照组的比率：0.78，90% CI，0.67-0.91）。HM3G与氢吗啡酮相比在口服和静脉注射氢吗啡酮后分别增加了50%（90% CI，25-79）和42%（90% CI，29-55）。利福平对药效学参数没有显著影响。
利福平显著降低口服和静脉注射氢吗啡酮的药物浓度。这种相互作用是由于氢吗啡酮的首过效应和全身代谢增加，过程可能涉及利福平诱导的尿苷-5'-二磷酸-葡萄糖醛酸苷转移酶。因此，在管理使用强酶诱导剂治疗的患者疼痛时，应考虑其增强氢吗啡酮消除的作用。
原始文献来源：Terhi J. Lohela, Satu Poikola, Mikko Neuvonen, et al. Rifampin Reduces the Plasma Concentrations of Oral and Intravenous Hydromorphone in Healthy Volunteers[J]. (Anesth Analg 2021;133:423–34).
Rifampin Reduces the Plasma Concentrations of Oral and Intravenous Hydromorphone in Healthy Volunteers
Background: Several opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin.
Methods: In this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuro-nide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration–time curve (AUC0–last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes.
Results: Rifampin reduced the AUC0–last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters.
Conclusions: Rifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5′-diphospho-glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.