A comprehensive pharmacokinetic strategy for systematic evaluation of whole interaction of different constituents in Astragali Radix -Fructus Corni to improve diabetic kidney disease

Astragali-Radix (the dried root of Astragalus mongholicus Bunge, AR) - Fructus Corni (the dried ripe fruit of Cornus officinalis Sieb. et Zucc., FC) has been used as a herb-pair remedy to treat diabetic kidney disease (DKD) for hundred years. Polysaccharides, saponins, and flavonoids in AR, and the iridoid glycosides in FC were deemed as the main bioactive constituents that can offer beneficial nephroprotective activities. A systematic evaluation of the nephroprotective effects of AR-FC herb pair, the main bioactive constituents extracted from the herb pair, and their combinations in different ratios was performed, CG6 (polysaccharides, flavonoids, saponins, and iridoid glycosides, in a ratio of 2:3:1:2) as the best compatibility proportion was screened out in our previous study. This study aimed to investigate the pharmacokinetic characteristics of AR-FC herb-pair in DKD rats, and explore the interactions between constituents from AR-FC and the rational compatibility of different constituents. The protective effect of AR-FC and CG6 on renal injury caused by DKD was first verified by histopathological examination. Then, an analytical method based on UHPLC-Q-TOF-MS and UHPLC-QqQ-MS/MS for qualitative and quantitative metabolites without reference standards was established and applied to pharmacokinetic (PK) studies in following different aspects: between single groups (polysaccharides, flavonoids, saponins and iridoid glycosides) and compatibility groups (AR-FC, CG6), in normal and DKD rats, in single-dose administration and long-term administration. Pathological observations confirmed that AR-FC could improve renal injury in DKD rats. PK profiles of nine prototypes and four metabolites in various groups were obtained, revealing the compatibility of multiple constitutes, pathological states, and long-term administration could alter PK characteristics of the main components from AR-FC, and promoting the absorption of them (Cmax, AUC0-t, and AUC0-t increased). Notably, co-administration of iridoid glycosides could significantly increase the absorption of flavonoids and saponins in vivo. The pharmacokinetics based on homologous compounds revealed that saponins first acted, then its initial metabolites affected flavonoids, and ultimately the metabolites of flavonoids influenced iridoid glycosides. This study demonstrated the existence of interactions between constituents from AR-FC herb-pair and the importance of their rational compatibility. It provides experi