Evaluation of pharmacokinetics and metabolism of three marine-derived piericidins for guiding drug lead selection.
10.1016/S1875-5364(25)60866-1
- Author:
Weimin LIANG
1
;
Jindi LU
1
;
Ping YU
1
;
Meiqun CAI
1
;
Danni XIE
1
;
Xini CHEN
1
;
Xi ZHANG
1
;
Lingmin TIAN
1
;
Liyan YAN
1
;
Wenxun LAN
1
;
Zhongqiu LIU
2
;
Xuefeng ZHOU
3
;
Lan TANG
4
Author Information
1. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 China.
2. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
3. CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China. Electronic address: xfzhou@scsio.ac.cn.
4. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 China. Electronic address: tl405@smu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Drug evaluation;
Drug lead selection;
Metabolism;
Pharmacokinetics;
Piericidin glycosides
- MeSH:
Animals;
Male;
Mice;
Aquatic Organisms/chemistry*;
Biological Availability;
Cytochrome P-450 Enzyme System/metabolism*;
Glucuronosyltransferase/metabolism*;
Microsomes, Liver/metabolism*;
Molecular Structure;
Biological Products/pharmacokinetics*;
Pyridines/pharmacokinetics*
- From:
Chinese Journal of Natural Medicines (English Ed.)
2025;23(5):614-629
- CountryChina
- Language:English
-
Abstract:
This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
