Pharmacokinetic/Pharmacodynamic Study of Salt-Processed product of Cuscutae Semen with Hepatoprotective Effects.

ABSTRACT

BACKGROUND: Salt-processed product of cuscutae semen (SCS), which is documented in Chinese pharmacopoeia (2020 edition), is one of the processed products of cuscustae semen. SCS possesses hepatoprotective effects. However, Pharmacokinetic / Pharmacodynamic (PK-PD) study of SCS with intervening acute liver injury (ALI) has not been reported yet. Effective constituents are still not well addressed. OBJECTIVE: This study was performed to study PK-PD properties with the purpose of linking SCS hepatoprotective effects to key therapeutic outlines to guide therapeutic use in clinical settings. METHODS: Rats were orally administered SCS after the acute liver injury model was established. Plasma biochemical analysis, antioxidative analysis, and liver histopathology were measured to evaluate the hepatoprotective effects of SCS. Blood samples were collected at different time points (0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 8 h, 12 h, 24 h) for PK/PD study after SCS administration. Contents of chlorogenic acid, hyperoside and astragalin were estimated by UHPLC-ESI-MS. The relationship between concentrations of chlorogenic acid, hyperoside, and astragalin and hepatoprotective effects was assessed by PK-PD modeling. RESULTS: The results showed that SCS ameliorated liver repair and decreased the serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST) markedly. Hepatic oxidative stress was inhibited by SCS, as evidenced by a decrease in malondialdehyde (MDA) and an increase in glutathione (GSH) and superoxide dismutase (SOD) in the liver. PK-PD correlation analysis indicated that concentrations of chlorogenic acid, hyperoside, and astragalin were negatively correlated with level of AST and ALT. CONCLUSION: The encouraging finding indicates that SCS has beneficial effects on CCl4-induced liver damage. Chlorogenic acid, hyperoside, and astragalin are three effective constituents to exert hepatoprotective effects while astragalin may have maximum pharmacological activity. PK-PD study reveals the positive relationship between drug concentration and action intensity of SCS against liver injury. This research provides a robust foundation for future studies.