Evaluation of Pharmacokinetics and Metabolism of Three Marine-derived Piericidins for Guiding Drug Lead Selection

To develop a good preclinical candidate by lead selection and optimization, the present study aims to explore the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), namely glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). Rapid absorption of PA and GPAs in mice were observed, with short half-life and low bioavailability. Glycosides and hydroxyl groups significantly accelerated the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs demonstrated metabolic instability by CYPs and UGTs in liver microsomes. The elimination rates of PA and GPAs by UGT1A7, UGT1A8, UGT1A9 and UGT1A10 were as high as 30-70%, making glucuronidation the primary metabolic pathway. The fast glucuronidation may contribute to the low bioavailability of GPAs. Although 13-OH-GPA had low bioavailability (2.69%), its distribution in kidney was higher (19.8%) than PA (10.0%) and GPA (7.3%), suggesting its superior biological effects in kidney diseases. To enhance its bioavailability, modifying the C-13 hydroxyl group seems to be a promising approach. In conclusion, this study provided valuable metabolic information for the development and optimization of marine-derived piericidins as promising drug leads for kidney disease.