Context: Total Glucosides of Paeony (TGP) capsule possesses various hepatoprotective activities. No study is available concerning TGP's concentration-effect relationship on hepatoprotection.
Objective: To establish a pharmacokinetics-pharmacodynamics (PK-PD) modelling on TGP capsule's hepatoprotection after a single oral administration in hepatic injury rats.
Materials and methods: Male Sprague-Dawley rats were divided into five groups (n = 6): control, model (hepatic injury), treated-H (2.82 g/kg), treated-M (1.41 g/kg), and treated-L (0.705 g/kg) groups. All treated groups rats were intragastrically administered a single dose. An LC-MS/MS method was applied to determine paeoniflorin (Pae) and albiflorin (Alb) in rat serum. The effects of single-dose TGP on serum alanine transaminase (ALT), aspartate transaminase (AST) and total bile acid (TBA) were evaluated in hepatic injury rats.
Results: Single dose (2.82, 1.41, or 0.705 g/kg) TGP capsule could real-time down-regulate serum TBA but not ALT and AST in hepatic injury rats within 20 h. An inhibitory effect Sigmoid Emax of PK-PD modelling was established using Pae and Alb as PK markers and serum TBA as effect index. Pharmacodynamic parameters were calculated. For treated-H, treated-M and treated-L group, respectively, E0 were 158.1, 226.9 and 245.4 μmol/L for Pae, 146.1, 92.9 and 138.4 μmol/L for Alb, Emax were 53.0, 66.0, and 97.1 μmol/L for Pae, 117.4, 249.7 and 60.0 μmol/L for Alb, and EC50 were 9.3, 5.2 and 2.7 μg/mL for Pae, 2.3, 0.8, and 0.8 μg/mL for Alb.
Discussion and conclusions: Serum TBA is a sensitive effect index for TGP's single dose PK-PD modelling, and it is potential for further multi-dose studies of TGP' effect on hepatic injury. The study provides valuable information for TGP's mechanistic research and rational clinical application.
Keywords: Paeoniflorin; TBA; albiflorin; concentration–effect relationship; effect index; hepatoprotection; serum biomarker.