Establishment of PK-PD combination model of effective components of Huangqi Liuyi Decoction based on a diabetic nephropathy rat model
Objective The PK-PD binding model of effective component(total astragaloside,total flavonoids of astragalus,astragalus polysaccharide,and glycyrrhizic acid,HLDC)of Huangqi Liuyi Decoction against diabetic nephropathy was established,and the dynamic changes of HLDC component in diabetic nephropathy rats and the relationship between HLDC component and drug effect were clarified.Methods The rat model of diabetic nephropathy was established by high-fat and high-sugar feed and streptozotocin(33 mg·kg-1)injected into the tail vein.After single or multiple oral administrations of HLDC(1.320 g kg-1),the plasma contents of astragaloside Ⅳ,ononin,formononetin,calycosin-7-O-beta-D-glucoside,calycosin and glycyrrhizic acid were determined by HPLC-MS/MS at different time points,and tumor necrosis factor-α(TNF-α),vascular endothelial growth factor(VEGF)and interleukin were detected by enzyme-linked immunosorbent assay(ELISA).The pharmacokinetic(PK)parameters of each component were fitted by using WinNonlin 8.2 software,and the aging relationship was fitted to get PD.The PK-PD model of HLDC is established according to PD parameters.Results The results of pharmacokinetics showed that compared with a single administration,the tmax of each component of the model rats was advanced after repeated administration except calycosin-7-O-beta-D-glucoside.T1/2 of each component was delayed.Except glycyrrhizic acid and calycosin,the AUC of all components increased.The pharmacodynamic results showed that the inhibitory effect of the drug increased first and then decreased while the drug concentration gradually decreased.Except for astragaloside Ⅳ,TNF-α,VEGF,and IL-18 in the single-dose group,the peak time of the drug effect was longer than that in the blood concentration,and there was a lag effect.PK-PD binding model showed that the blood concentration of six components in single and multiple doses of HLDC and their pharmacodynamic data could be well fitted.The corresponding drug effect value can be calculated by the blood concentration of six components such as astragaloside Ⅳ,and the corresponding blood concentration can also be calculated according to the drug effect value.Conclusion The results of the PK-PD model are by the Sigmoid-Emax model,and the levels of inflammatory factors such as TNF-α,VEGF,and IL-18 have a good correlation with the concentrations of six blood component drugs such as astragaloside Ⅳ in HLDC.The active components of HLDC play a role in preventing and treating diabetic nephropathy and significantly improving renal function,which may be related to inhibiting the secretion of inflammatory factors such as TNF-α,VEGF,and IL-18.
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