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

作者：Chhonker Yashpal S; Chandasana Hardik; Mukkavilli Rao; Prasad Yarra Durga; Laxman Tulsankar Sachin; Vangala Subrahmanyam; Bhatta Rabi S

来源：Drug Testing and Analysis, 2016, 8(9): 966-975.

DOI：10.1002/dta.1885

<jats:p>Guggulsterone is a racemic mixture of two stereoisomers (<jats:italic>E</jats:italic>‐ and <jats:italic>Z</jats:italic>‐), obtained from the gum resin of <jats:italic>Commiphora mukul</jats:italic> and it is marketed as an antihyperlipidemic drug. The aim of our study was to assess the <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> absorption, distribution, metabolism, and excretion (ADME) properties namely solubility, <jats:italic>in vitro</jats:italic> metabolism, plasma protein binding and oral pharmacokinetic studies of <jats:italic>E</jats:italic>‐ and <jats:italic>Z</jats:italic>‐guggulsterone. <jats:italic>In vitro</jats:italic> metabolism experiments were performed by using rat liver and intestinal microsomes. <jats:italic>In vitro</jats:italic> intrinsic clearance (CL<jats:sub>int</jats:sub>) was found to be 33.34 ± 0.51 and 39.23 ± 8.12 μL/min/mg protein in rat liver microsomes for <jats:italic>E</jats:italic>‐ and <jats:italic>Z</jats:italic>‐isomers, respectively. Plasma protein binding was determined by equilibrium dialysis method and <jats:italic>in vivo</jats:italic> pharmacokinetic studies were performed in male Sprague Dawley (SD) rats. Both isomers were highly bound to rat plasma proteins (&gt;95% bound). Plasma concentration of <jats:italic>E</jats:italic>‐ 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 <jats:italic>E</jats:italic>‐isomer was 2.79 ± 0.73 compared to 3.01 ± 0.61 L/h/kg for <jats:italic>Z</jats:italic>‐isomer, indicating no significant difference (student <jats:italic>t</jats:italic> test; p &lt;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.

• 出版日期2016-9