A Comparative Pharmacokinetic Study by UHPLC-MS/MS of Main Active Compounds after Oral Administration of Zushima-Gancao Extract in Normal and Adjuvant-Induced Arthritis Rats.

Jinjun Shan,Linxiu Peng,An Kang,Liuqing Di,Tong Xie,Wenjuan Qian,Lianghui Chen

doi:10.3390/molecules23010227

Abstract

A sensitive and rapid ultra high-performance liquid-chromatography tandem mass spectrometry (UHPLC-MS/MS) method has been applied to investigate the influence of rheumatoid arthritis (RA) on the pharmacokinetics of nine analytes (daphnetin, daphnoretin, 7-hydroxycoumarin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, glycyrrhizin, and glycyrrhetinic acid), which are major active components in Zushima-Gancao extract. The analytes and internal standard (IS) were separated in a Hypersil Gold C18 column and detected on a triple-stage quadrupole mass spectrometer using the validated method. All analytes exhibited good linearities (R2 > 0.98), and the lower limit of quantification (LLOQs) were sufficient for quantitative analysis. Intra- and inter-batch precision were all within 14.96% while the accuracy of nine analytes ranged from −17.99 to 14.48%, and these results were all within acceptance criteria. The extraction recoveries, matrix effects, and stabilities were all satisfactory. Main pharmacokinetic parameters of each compound were compared, and significant differences were found in parameters of daphnetin, daphnoretin, liquiritin, isoliquiritin, isoliquiritigenin, glycyrrhizin, and glycyrrhetinic acid, especially the last one, between the two groups. Therefore, adjuvant-induced arthritis has different effects on the pharmacokinetics of ingredients in Zushima-Gancao extract. The comparative pharmacokinetic study between normal and adjuvant-induced arthritis rats might provide more comprehensive information to guide the clinical usage of Zushima-Gancao extract for treating RA.

Highlights

Rheumatoid arthritis (RA) is a chronic systemic disease accompanied by the destruction of joints, but its etiology has remained unknown [1]
No significant endogenous interference was observed at the retention times of the analytes and internal standard (IS) from the chromatograms of blank plasma samples (Figure 1a), blank plasma samples spiked with mixed standards and IS (Figure 1b), plasma samples obtained from normal rats (Figure 1c), and plasma samples obtained from adjuvant-induced arthritis (AA) rats (Figure 1d) collected from different rats after administration of Zushima-Gancao extract
The specificity was assessed to ensure no endogenous interference. It was carried out by comparing the chromatograms of blank plasma samples, blank plasma samples spiked with mixed standards and IS, plasma samples obtained from normal rats, and plasma samples obtained from AA

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic systemic disease accompanied by the destruction of joints, but its etiology has remained unknown [1]. Western medicine, including nonsteroidal anti-inflammatory drugs (NSAIDS) [2] and biologics [3], has greatly improved the clinical efficacy of medicine acting against RA. The adverse reactions and toxicities associated with these drugs [4,5,6] have promoted the development of traditional Chinese herbal medicine (TCHM), such as Molecules 2018, 23, 227; doi:10.3390/molecules23010227 www.mdpi.com/journal/molecules. These TCHMs are featured with high pharmacological activities and have been widely used to treat RA for decades [7,8]. Zushima is the root cortex and shoot bark of Daphne giraldii Nitsche, D. tangutica Maxim, and D. retusa Hemsl. In the past several decades, much more attention has been paid to the chemical and biological studies of Zushima [7,9]. It was reported that coumarins and diterpenes were the main bioactive components and the former has function of anti-inflammation and painkilling [10,11,12]

Methods

Results

Conclusion