Assessment of in vitro metabolic stability, plasma protein binding, and pharmacokinetics of E- and Z-guggulsterone in rat.

Guggulsterone is a racemic mixture of two stereoisomers (E- and Z-), obtained from the gum resin of Commiphora mukul and it is marketed as an antihyperlipidemic drug. The aim of our study was to assess the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties namely solubility, in vitro metabolism, plasma protein binding and oral pharmacokinetic studies of E- and Z-guggulsterone. In vitro metabolism experiments were performed by using rat liver and intestinal microsomes. In vitro intrinsic clearance (CLint ) was found to be 33.34 ± 0.51 and 39.23 ± 8.12 μL/min/mg protein in rat liver microsomes for E- and Z-isomers, respectively. Plasma protein binding was determined by equilibrium dialysis method and in vivo pharmacokinetic studies were performed in male Sprague Dawley (SD) rats. Both isomers were highly bound to rat plasma proteins (>95% bound). Plasma concentration of E- and Z-isomers decreased rapidly following oral administration and were eliminated from systemic circulation with a terminal half-life of 0.63 ± 0.25 and 0.74 ± 0.35 h, respectively. The clearance (CL) for E-isomer was 2.79 ± 0.73 compared to 3.01 ± 0.61 L/h/kg for Z-isomer, indicating no significant difference (student t test; p <0.05) in their elimination.The pharmacokinetics of both isomers was characterized by extensive hepatic metabolism as seen with rat liver microsomes with high clearance and low systemic availability in rats. In brief, first-pass metabolism seems to be responsible factor for low bioavailability of guggulsterone. Copyright © 2015 John Wiley & Sons, Ltd.