Nebivolol hydrochloride and its impurities induce pseudo‐allergic reactions via mast cell activation

Nebivolol hydrochloride is a third‐generation β‐blocker commonly used to treat cardiovascular diseases. However, it has been reported to induce allergic reactions in clinical use which deserves much attention. Therefore, this study focused on the ability of two isomers of nebivolol and chiral isomer impurities to induce allergic reactions. Our findings demonstrate that both nebivolol and two isomeric impurities can activate mast cell degranulation in vitro and show significant retention on Mas‐related G‐protein‐coupled receptor X2 (MRGPRX2)‐HEK293 cell membrane chromatography. These effects were further validated in vivo, where nebivolol and impurity IP‐3 were observed to cause toe swelling and mast cell degranulation in mice. Molecular docking studies revealed interactions between these compounds and key amino acids of MRGPRX2, suggesting a mechanism for the induced allergic reactions. This work lays the foundation for improving the clinical safety of nebivolol.