AUTHOR=Huang Jing , Chen Ruixing , Zhou Jie , Zhang Qing , Xue Cun , Li Yueting , Zheng Lin , Huang Yong , Wang Qun , Chen Yi , Gong Zipeng 

TITLE=Comparative pharmacokinetic study of the five anti-inflammatory active ingredients of Inula cappa in a normal and an LPS-induced inflammatory cell model

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.981112

DOI=10.3389/fphar.2022.981112

ISSN=1663-9812

ABSTRACT=<p><italic>Inula cappa</italic> is a commonly used medicine in the Miao area of Guizhou Province in China. We established an <italic>in vitro</italic> inflammatory model of mouse macrophage RAW264.7 cells to study the different pharmacokinetics of five anti-inflammatory active ingredients in the <italic>I. cappa</italic> extract namely luteolin (LUT), chlorogenic acid (CA), cryptochlorogenic acid (CCA), 3,4-dicaffeoylquinic acid (3,4-DCQA) and 4,5-dicaffeoylquinic acid (4,5-DCQA), in a normal and an inflammatory cell model. First, RAW264.7 cells were treated <italic>in vitro</italic> with l μg/mL lipopolysaccharide (LPS) for 24 h to establish an inflammatory cell model. Then, the pharmacokinetic characteristics of the five ingredients were compared in normal and inflammatory cells after treatment with 200 μg/ml and 800 μg/ml of <italic>I. cappa</italic> extracts. After treatment with 1 μg/ml LPS for 24 h, the volume of RAW264.7 cells was increased, the morphology was changed, the antennae were obvious, and the secretion of inflammatory factors nitric oxide and TNF-α was increased. The pharmacokinetics results showed that the five ingredients in normal and inflammatory cells exhibited an increase in C<sub>max</sub> and AUC values with increasing doses, and the C<sub>max</sub> and AUC values of five ingredients were positively correlated with the extract concentration. Each of these five ingredients presented nonlinear pharmacokinetic characteristics. After treatment with 200 μg/ml of <italic>I. cappa</italic> extract, the uptake of five ingredients increased in inflammatory cells, T<sub>max</sub> was prolonged, MRT and t<sub>1/2</sub> were prolonged, and CL_F and Vz_F were decreased, while after treatment with 800 μg/ml of <italic>I. cappa</italic> extract, the uptake of five ingredients decreased, T<sub>max</sub> was prolonged, absorption was faster, and MRT and t<sub>1/2</sub> were prolonged. The five analyzed components in <italic>I. cappa</italic> extract exerted different effects on normal cells and LPS-induced inflammatory cells. Compared to normal cells, the uptake of five ingredients in inflammatory cells was faster and the AUC and C<sub>max</sub> values increased with increasing doses, showing a dose-dependent nonlinear pharmacokinetic profile. These results indicate that the pharmacokinetic effects of the five analyzed ingredients in <italic>I. cappa</italic> extract are changed in the inflammatory state.</p>