New Drug Development Center, Daegu‒Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.
Molecules. 2018 Jun 17;23(6):1470. doi: 10.3390/molecules23061470.
Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol) and magnolol (4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol) are the major active polyphenol constituents of (Magnoliaceae) bark, which has been widely used in traditional Chinese medicine (Houpu Tang) for the treatment of various diseases, including anxiety, stress, gastrointestinal disorders, infection, and asthma. The aim of this study was to investigate the direct effects of honokiol and magnolol on hepatic CYP1A and 2C-mediated metabolism in vitro using rat liver microsomes and in vivo using the Sprague-Dawley rat model. Honokiol and magnolol inhibited in vitro CYP1A activity (probe substrate: phenacetin) more potently than CYP2C activity (probe substrate: diclofenac): The mean IC values of honokiol for the metabolism of phenacetin and diclofenac were 8.59 μM and 44.7 μM, while those of magnolol were 19.0 μM and 47.3 μM, respectively. Notably, the systemic exposure (AUC and C) of phenacetin, but not of diclofenac, was markedly enhanced by the concurrent administration of intravenous honokiol or magnolol. The differential effects of the two phytochemicals on phenacetin and diclofenac in vivo pharmacokinetics could at least be partly attributed to their lower IC values for the inhibition of phenacetin metabolism than for diclofenac metabolism. In addition, the systemic exposure, CL, and V of honokiol and magnolol tended to be similar between the rat groups receiving phenacetin and diclofenac. These findings improve our understanding of CYP-mediated drug interactions with and its active constituents.
和厚朴酚（2-（4-羟基-3-丙烯基-2-苯基）-4-丙烯基-苯酚）和厚朴酚（4-烯丙基-2-（5-烯丙基-2-羟基-苯基）苯酚）是厚朴（木兰科）树皮的主要活性多酚成分，在中国传统医学（厚朴汤）中广泛用于治疗各种疾病，包括焦虑、压力、胃肠道疾病、感染和哮喘。本研究旨在使用大鼠肝微粒体和 Sprague-Dawley 大鼠模型体内研究和厚朴酚和厚朴酚对肝 CYP1A 和 2C 介导的代谢的直接影响。和厚朴酚和厚朴酚对 CYP1A 活性（探针底物：苯乙酮）的抑制作用比 CYP2C 活性（探针底物：双氯芬酸）更强：和厚朴酚代谢苯乙酮和双氯芬酸的平均 IC 值分别为 8.59 μM 和 44.7 μM，而厚朴酚的 IC 值分别为 19.0 μM 和 47.3 μM。值得注意的是，静脉注射和厚朴酚或厚朴酚同时给药显著增强了苯乙酮的全身暴露（AUC 和 C），但不增强双氯芬酸的全身暴露。两种植物化学物质对体内苯乙酮和双氯芬酸药代动力学的不同影响至少部分归因于它们对苯乙酮代谢的抑制作用的 IC 值低于对双氯芬酸代谢的抑制作用的 IC 值。此外，接受苯乙酮和双氯芬酸的大鼠组之间，和厚朴酚和厚朴酚的全身暴露、CL 和 V 趋于相似。这些发现提高了我们对和厚朴酚及其活性成分与 CYP 介导的药物相互作用的理解。
