In-vitro metabolism, CYP profiling and metabolite identification of E- and Z- guggulsterone, a potent hypolipidmic agent

The polyphenol E- and Z-gugggulsterone (GS) is an antagonist ligand for the Farnesoid X Receptor (FXR) and known to possess potent hypolipidemic properties as shown in various preclinical and clinical studies. In the present study, we examined drug-like properties of GS by assessing the isomers plasma protein binding, metabolic stability, CYP profiling, CYP inhibition, and phase I and II metabolite identification of GS using liver microsomes and S9 fractions. GS followed Lipinski and Veber rules and were substrates of CYP3A CYP2C19 and CYP2D6 isoforms. GS was also found to be an inhibitor of CYP2C19 with an IC50 value of 2.1 μM. GS showed high plasma protein binding (<96%), and low to moderate binding with human serum albumin (∼70%). Unbound intrinsic clearances (CLint, in-vitro) was determined to be low at 0.029 ± 0.0009 and 0.027 ± 0.008 mL/min/mg protein for E- and Z-isomer, respectively in human liver microsomes. Nineteen phase I and II metabolites were identified and hydroxylation was found to be major metabolic pathway using human liver microsomes and S9 fractions. The results of in-vitro drug-metabolism studies provide impetus for further structural modification of this pharmacophore in order to improve the stability of drugs with potent hypolipidemic effects.