Pharmacokinetics and Metabolism of 4‐O‐Methylhonokiol in Rats

The purpose of this study was to characterize the pharmacokinetics and metabolism of 4‐ O ‐methylhonokiol in rats. The absorption and disposition of 4‐ O ‐methylhonokiol were investigated in male Sprague–Dawley rats following a single intravenous (2 mg/kg) or oral (10 mg/kg) dose. Its metabolism was studied in vitro using rat liver microsomes and cytosol. 4‐ O ‐Methylhonokiol exhibited a high systemic plasma clearance and a large volume of distribution. The oral dose gave a peak plasma concentration of 24.1±3.3 ng/mL at 2.9±1.9 h and a low estimated bioavailability. 4‐ O ‐Methylhonokiol was rapidly metabolized and converted at least in part to honokiol in a concentration‐dependent manner by cytochrome P450 in rat liver microsomes, predicting a high systemic clearance consistent with the pharmacokinetic results. It was also shown to be metabolized by glucuronidation and sulfation in rat liver microsomes and cytosol, respectively. 4‐ O ‐Methylhonokiol showed a moderate permeability with no apparent vectorial transport across Caco‐2 cells, suggesting that intestinal permeation process is not likely to limit its oral absorption. Taken together, these results suggest that the rapid hepatic metabolism of 4‐ O ‐methylhonokiol could be the major reason for its high systemic clearance and low oral bioavailability. Copyright © 2013 John Wiley & Sons, Ltd.