An Investigation of Pharmacokinetic Interaction of Vericiguat with Apigenin based on a Newly Developed Ultra-performance Liquid Chromatography-tandem Mass Spectrometry Assay

Abstract

Background: Vericiguat, as a new stimulator of soluble guanylate cyclase (sGC), was recently approved as a first-in-class treatment for reducing risks in patients with ejection fraction less than 45 percent and heart failure (HF) in the USA. Objective: The main aim of the present experiment was to establish an acceptable, sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentration levels of vericiguat in rats, and to further evaluate the effect of apigenin on the metabolism of vericiguat in vivo. Method: In sample processes, acetonitrile was finally chosen for quickly precipitating protein. The levels of vericiguat in plasma were analyzed by a Xevo TQ-S triple quadrupole tandem mass spectrometry (Milford, MA, USA) in a positive ion mode. Results: The scope of the calibration standard for vericiguat ranged from 0.5 to 1000 ng/mL, where a great linearity was acceptable. The lower limit of quantification (also called LLOQ) of vericiguat presented the sensitivity of this assay was evaluated as low as 0.5 ng/mL. Additionally, selectivity, accuracy and precision, extraction recovery, matrix effect, and stability were all verified. Subsequently, this approach also supported to assess the plasmatic concentrations of vericiguat from an interaction survey on herb-- drug, in which oral administration of apigenin (20 mg/kg) obviously increased the plasmatic levels of vericiguat and altered the pharmacokinetics of vericiguat in rats. Conclusion: These results would help us to further understand the pharmacokinetic properties of vericiguat when co-administration with apigenin, and to avoid unexpected clinical risks in the future.