Bio-Evaluation Center, KRIBB, Chungbuk, Republic of Korea; College of Pharmacy, Chungbuk National University, Chungbuk, Republic of Korea.
Phytother Res. 2014 Apr;28(4):568-78. doi: 10.1002/ptr.5033. Epub 2013 Jul 3.
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.
本研究旨在表征 4-O-甲基厚朴酚在大鼠体内的药代动力学和代谢特征。雄性 Sprague-Dawley 大鼠单次静脉（2mg/kg）或口服（10mg/kg）给予 4-O-甲基厚朴酚后，研究了其吸收和处置情况。采用大鼠肝微粒体和胞质体进行体外代谢研究。4-O-甲基厚朴酚表现出高的全身血浆清除率和大的分布容积。口服剂量在 2.9±1.9h 时达到 24.1±3.3ng/mL 的峰值血浆浓度，估计生物利用度较低。4-O-甲基厚朴酚在大鼠肝微粒体中被细胞色素 P450 以浓度依赖的方式迅速代谢，并至少部分转化为厚朴酚，这与药代动力学结果一致，表明其具有较高的全身清除率。此外，它还在大鼠肝微粒体和胞质体中分别通过葡萄糖醛酸化和硫酸化代谢。4-O-甲基厚朴酚显示出中等的通透性，在 Caco-2 细胞中没有明显的载体转运，这表明肠道渗透过程不太可能限制其口服吸收。综上所述，这些结果表明 4-O-甲基厚朴酚的快速肝脏代谢可能是其高全身清除率和低口服生物利用度的主要原因。
