From the Department of Clinical Pharmacology, Faculty of Medicine.
Department of Anaesthesiology, Intensive Care Medicine, and Pain Medicine, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
Anesth Analg. 2021 Aug 1;133(2):423-434. doi: 10.1213/ANE.0000000000005229.
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.
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-glucuronide (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.
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.
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.
几种阿片类药物通过诱导型细胞色素 P450（CYP）3A 同工酶代谢。与药物代谢的强诱导剂如利福平合用，可显著降低这些阿片类药物的全身暴露量。由于氢吗啡酮的 CYP 代谢作用并不重要，因此我们研究了在同时接受典型酶诱导剂利福平的患者中，氢吗啡酮是否会成为有效的镇痛剂。
在这项配对、随机、交叉研究中，12 名参与者接受了 8 天的口服安慰剂或利福平治疗。第 6 天给予口服氢吗啡酮（2.6mg），第 8 天给予静脉注射氢吗啡酮（0.02mg/kg）。在 24 小时内测量氢吗啡酮和氢吗啡酮-3-葡萄糖醛酸（HM3G）的血浆浓度，并在 6 小时内评估精神运动反应，包括药物效应感知、瞳孔直径变化和冷加压阈值。我们的主要结局是在利福平或安慰剂预处理后，口服和静脉注射氢吗啡酮的 AUC0-last 变化。药效动力学参数和其他药代动力学参数作为次要结局进行分析。
利福平使口服和静脉注射氢吗啡酮的 AUC0-last 分别降低了 43%（与对照相比的比值：0.57，90%置信区间[CI]：0.50-0.65）和 26%（与对照相比的比值：0.74，90%CI：0.69-0.79）。口服氢吗啡酮的最大浓度降低了 37%（与对照相比的比值：0.63，90%CI：0.55-0.72），口服生物利用度从 33%降至 26%（与对照相比的比值：0.78，90%CI：0.67-0.91）在利福平阶段与安慰剂相比。口服和静脉注射氢吗啡酮后，HM3G-氢吗啡酮比值分别增加了 50%（90%CI：25-79）和 42%（90%CI：29-55）。利福平对药效动力学参数无显著影响。
利福平显著降低了口服和静脉注射氢吗啡酮的浓度。这种相互作用是由于氢吗啡酮的首过代谢和全身代谢增加所致，可能涉及利福平诱导尿苷 5'-二磷酸葡萄糖醛酸基转移酶的酶。在管理接受强酶诱导剂治疗的患者的疼痛时，应考虑增强氢吗啡酮的消除。
