Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Clin Pharmacol Ther. 2021 Jun;109(6):1505-1516. doi: 10.1002/cpt.2141. Epub 2021 Jan 19.
Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance.
甲灭酸是一种在某些国家广泛使用的镇痛解热药物。先前的研究表明，甲灭酸可诱导细胞色素（CYP）2B6，可能还可诱导 CYP3A4。到目前为止，尚不清楚甲灭酸是否还会诱导其他 CYP 以及通过何种机制。因此，我们采用表型分析鸡尾酒方法，在 12 名健康男性受试者中，在每天接受 3 g 甲灭酸治疗 1 周前后，评估了 6 种不同 CYP 的活性。此外，我们还在 HepaRG 细胞中研究了甲灭酸是否通过与组成型雄烷受体（CAR）或孕烷 X 受体（PXR）相互作用来诱导 CYP。在临床研究中，我们证实了甲灭酸对 CYP2B6（依非韦伦的血药浓度时间曲线下面积（AUC）减少 79%）和 3A4（咪达唑仑 AUC 减少 68%）的适度诱导。此外，甲灭酸还轻度诱导 CYP2C9（氟比洛芬 AUC 减少 22%）和中度诱导 CYP2C19（奥美拉唑 AUC 减少 66%），但不改变 CYP2D6 活性。此外，甲灭酸还轻度抑制 CYP1A2 活性（咖啡因 AUC 增加 1.79 倍）。我们在 HepaRG 细胞中证实了这些结果，其中甲灭酸的主要代谢物 4-MAA 诱导了 CYP2B6、2C9、2C19 和 3A4 的 mRNA 表达。在 PXR 或 CAR 稳定敲除的 HepaRG 细胞中，我们可以证明 4-MAA 诱导 CYP 的作用依赖于 CAR，而不依赖于 PXR。总之，甲灭酸通过与 CAR 相互作用并抑制 CYP1A2 而成为广泛的 CYP 诱导剂。鉴于甲灭酸的广泛使用，这些发现具有重要的临床意义。
