Effect of Ling-Gui-Zhu-Gan decoction major components on the plasma protein binding of metoprolol using UPLC analysis coupled with ultrafiltration

Abstract

Using traditional Chinese medicine formula Ling-Gui-Zhu-Gan decoction (LGZGD) plus selective β₁-adrenergic receptor inhibitor metoprolol to treat arrhythmia of coronary heart disease can significantly improve efficiency with no adverse reactions. However, the effect of major components of LGZGD on the plasma protein binding of metoprolol is unclear. Firstly, this study aimed to computationally predict the molecular interactions between metoprolol, the major components of LGZGD, and bovine serum albumin (BSA). Secondly, the plasma protein binding of metoprolol combined with major components of LGZGD was investigated by UPLC analysis coupled with ultrafiltration. The MOE (2008.10) software package was used to investigate the molecular interactions among metoprolol, the major components of LGZGD, and BSA. Using in vitro experiments, BSA was separately spiked with a mixtures of metoprolol and the major components of LGZGD. The results showed that metoprolol interacted with BSA mainly through arene–arene interactions, as did cinnamic acid and liquiritin. However, the energy scores of cinnamic acid and liquiritin were lower than that of metoprolol. There were no interactions between metoprolol and the major components of LGZGD. Further studies in vitro showed that the presence of the major components of LGZGD did not change the plasma protein binding of metoprolol. We adopted molecular docking to predict the drug–herb plasma protein binding interactions of metoprolol and then used ultrafiltration to verify the docking results. There were no drug–herb interactions between metoprolol and LGZGD in BSA, which indicated that this combination therapy might be safe and feasible.