Pharmacokinetics of Sinapic Acid from Stir-fried Raphani Semen in Rats and Its PK-PD Correlation Analysis / 中国实验方剂学杂志

ABSTRACT

Objective:To study the pharmacokinetics of sinapic acid from stir-fried Raphani Semen in normal rats and the correlation between pharmacokinetics-pharmacodynamics (PK-PD) in asthma rats. Method:Normal rats received 4.5, 9, 18 g·kg-1 of stir-fried Raphani Semen by oral administration, respectively. Blood was taken from ophthalmic venous plexus at different time points according to the experimental design, the plasma concentration of sinapic acid was analyzed by UHPLC-MS/MS, and data analysis was performed using DAS 3.2.8 software to obtain the pharmacokinetic parameters. Rat asthma model was established by intraperitoneal injection of ovalbumin with aluminum hydroxide, and treated with ethanol extract of stir-fried Raphani Semen (low and high doses of 4.5, 9 g·kg-1). After treatment for 3 weeks, taking blood at different time points, plasma and serum were separated. UHPLC-MS/MS was established for the determination of plasma concentration of sinapic acid, contents of interleukin-5 (IL-5), immunoglobuin E (IgE), tumor necrosis factor-α (TNF-α) in serum at different time points were detected by enzyme-linked immunosorbent assay (ELISA), DAS 3.2.8 software was used for PK-PD model fitting and data analysis. Result:After normal rats were administrated with low, medium and high doses of stir-fried Raphani Semen, the peak concentration (Cmax) of sinapic acid in plasma were (29.35±10.32), (62.70±27.47), (137.33±40.95) μg·L-1, its area under the curve (AUC0-t) were (92.83±27.16), (240.74±75.09), (633.95±195.88) μg·L-1·h, its peak time (Tmax) were (2.58±0.80), (3.00±0), (5.50±1.23) h, respectively. Compared with the low dose group, AUC0-t and mean retention time (MRT0-t) were all increased in the medium and high dose groups, showing statistical differences (P<0.05, P<0.01). The linear relationship of AUC0-t in sinapic acid was good within the dose range of 4.5-18 g·kg-1. After treating with ethanol extract of stir-fried Raphani Semen for 0.083, 0.167 h, compared with the model group of asthmatic rats, serum levels of IL-5, IgE, TNF-α of the medication groups were decreased to different degrees (P<0.05, P<0.01). Cmax of sinapic acid in the low and high dose groups were (58.43±29.94), (61.16±18.79) μg·L-1, its AUC0-t were (188.75±37.07), (247.90±36.89) μg·L-1·h, respectively. AUC0-t, apparent volume of distribution (Vz/F) and clearance rate (CLz/F) all increased significantly with the increase of dose. The best pharmacokinetic model of sinapic acid was fitted as a one-compartment model for extravascular administration, PK-PD model may be applicable to indirect connection model. Conclusion:The plasma concentration of sinapic acid is correlated with contents of IL-5, IgE and TNF-α, dosage and functional state (pathological or physiological state) can affect the pharmacokinetic behavior of sinapic acid from stir-fried Raphani Semen in rats, and it has a certain correlation with the anti-asthmatic effect.