A pharmacokinetics–pharmacodynamics study of single-dose total glucosides of paeony capsule on reducing serum total bile acid in hepatic injury rats

Abstract

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 E_max 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, E_max 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
• albiflorin
• hepatoprotection
• serum biomarker
• effect index
• TBA
• concentration–effect relationship

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This project was financially supported by Natural Science Foundation of Zhejiang Province [LY18H280011], Science and Technology Planning Project of Jiaxing [2020AY10022], Public Welfare Technology Application Research Project of Zhejiang Province [2015C37084, LGF18H160034], National Natural Science Foundation of China [81503338, 81872220], and the Grant of the Jiaxing University B Key Academic Subject (Pharmaceutical).