摘要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 preclin-ical 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 kid-ney disease.