Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Hospital Pharmacy, Heidelberg University Hospital, Im Neuenheimer Feld 670, 69120, Heidelberg, Germany.
Br J Clin Pharmacol. 2023 Aug;89(8):2458-2464. doi: 10.1111/bcp.15720. Epub 2023 Apr 1.
In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated.
Using repeated oral microdoses (30 μg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration-time curve from 2-4 h: AUC and estimated partial metabolic clearance: eCl ) before, at steady-state, and after discontinuation of 3 × 1000 mg metamizole/day orally for 8 days.
Significant changes in pharmacokinetic parameters were detected already 3 days after start of metamizole treatment. At the steady-state of enzyme induction, the geometric mean ratio of midazolam AUC was substantially reduced to 0.18 (90% confidence interval: 0.14-0.24) with a corresponding 5.43-fold (4.15-7.10) increase of eCl . After discontinuation of metamizole, the changes slowly recovered, but were still significant at the end of the observation period on the fifth day after discontinuation of metamizole therapy (AUC reduced to 0.50 [0.41-0.63] and eCl 1.99-fold increased [1.60-2.47, P < 0.05]).
Metamizole acts as a strong inducer of CYP3A already few days after start of metamizole administration and, thus, should be avoided in patients using drugs with narrow therapeutic index and major clearance via CYP3A. If their administration is essential, close monitoring and dose adjustment of comedication should be performed as early as the first week after the initiation and after discontinuation of metamizole therapy.
在各年龄段患者中，扑热息痛是一种常用的镇痛药。最近，扑热息痛被确定为细胞色素 P450（CYP）3A 活性的诱导剂之一，但尚未评估这种相互作用的时间过程。
我们使用重复口服微剂量（30μg）的 CYP3A 指数底物咪达唑仑，评估在开始使用扑热息痛 3×1000mg/天，连续 8 天，以及在停药 3 天后、稳态时和停药 8 天后，咪达唑仑药代动力学（2-4 小时的浓度-时间曲线下面积：AUC 和估计的部分代谢清除率：eCl）的变化。
在开始使用扑热息痛治疗后 3 天就检测到了药代动力学参数的显著变化。在酶诱导的稳态时，咪达唑仑 AUC 的几何平均比值显著降低至 0.18（90%置信区间：0.14-0.24），同时 eCl 增加了 5.43 倍（4.15-7.10）。停用扑热息痛后，变化缓慢恢复，但在停用扑热息痛治疗后第 5 天观察结束时仍有显著变化（AUC 降低至 0.50[0.41-0.63]，eCl 增加 1.99 倍[1.60-2.47，P<0.05]）。
扑热息痛在开始使用扑热息痛几天后就表现出对 CYP3A 的强烈诱导作用，因此，在使用具有窄治疗指数和主要通过 CYP3A 清除的药物的患者中应避免使用扑热息痛。如果必须使用这些药物，应在开始使用和停用扑热息痛治疗后第一周就开始密切监测并调整合并用药的剂量。
