This study investigates the pharmacokinetics and metabolic characteristics of three marinederived piericidins as potential drug leads for kidney disease:piericidin A(PA)and its two glycosides(GPAs),glucopiericidin A(G...This study investigates the pharmacokinetics and metabolic characteristics of three marinederived 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.展开更多
基金supported by the Special Project for Marine Economic Development of Department of Natural Resources of Guangdong Province(No.GDNRC[2024]25)National Natural Science Foundation of China(Nos.82274002,U20A20101)+1 种基金Guangdong Local Innovation Team Program(No.2019BT02Y262)Science and Technology Innovation Project of Guangdong Medical Products Administration(Nos.S2021ZDZ042,2023ZDZ06,2024-ZDZ08,2024A1515012477)。
文摘This study investigates the pharmacokinetics and metabolic characteristics of three marinederived 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.
