In Vitro Metabolism and Disposition of Honokiol in Rat and Human Livers
In Vitro Metabolism and Disposition of Honokiol in Rat and Human Livers
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DOI：
10.1002/jps.22536
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发表时间：
2011-08-01
影响因子：
3.8
通讯作者：
Jaeger, Walter
中科院分区：
文献类型：
--
作者：
Boehmdorfer, Michaela;Maier-Salamon, Alexandra;Jaeger, Walter
本文研究了厚朴主要成分和厚朴酚在大鼠和人肝脏中的生物转化。当分离时，大鼠肝脏灌注10 μ M honokaline和两种代谢产物，即羟基化honokaline与葡萄糖醛酸和硫酸（M1）和honokaline monoglucuronide（M2）共轭，定量胆汁和灌注液中的高效液相色谱法。和厚朴酚在大鼠肝脏中的肝脏提取率和清除率非常高（E：分别为0.99 +/- 0.01和35.8 +/- 0.04 mL/min），导致生物利用度非常低（F = 0.007 +/- 0.001）。在人肝微粒体中M2的形成也非常高效[V（max）/K（m）= 78.1 +/- 6.73 mu L/（min mg）]，这似乎主要由UDP-葡萄糖醛酸转移酶1A 1、A3、1A 8和1A 10催化，表明肝和肝外葡萄糖醛酸化。人肝胞质溶胶将和厚朴酚单硫酸化为次要代谢物和厚朴酚单硫酸盐[V（max）/K（m）= 27.9 +/- 4.33 μ L/（min mg）]不太明显，并且由磺基转移酶1A 1 * 1、1A 1 * 2、1A 2、1A 3、1B 1和1 E1介导。然而，P450介导的肝微粒体对和诺啡肽的氧化低于检测限。总之，本研究确定了葡萄糖醛酸化和硫酸化是大鼠和人肝脏中和厚朴酚的主要代谢途径，表明其对体内清除的主要贡献。(C)2011 Wiley-Liss，Inc.和American Pharmacologist Association J Pharm Sci 100：3505-3516，2011
The biotransformation of honokiol, a major constituent of the bark of Magnolia officinalis, was investigated in rat and human livers. When isolated, rat livers were perfused with 10 mu M honokiol and two metabolites, namely hydroxylated honokiol conjugated with glucuronic and sulfuric acid (M1) and honokiol monoglucuronide (M2), were quantified in bile and perfusate by high-performance liquid chromatography. The hepatic extraction ratio and clearance of honokiol was very high in rat liver (E: 0.99 +/- 0.01 and 35.8 +/- 0.04 mL/min, respectively) leading to very low bioavailability (F = 0.007 +/- 0.001). M2 formation was also highly efficient in human liver microsomes [V(max)/K(m) = 78.1 +/- 6.73 mu L/(min mg)], which appeared to be catalyzed mainly by UDP-glucuronosyltransferases 1A1, A3, 1A8, and 1A10, indicating hepatic and extrahepatic glucuronidation. Monosulfation of honokiol to the minor metabolite honokiol monosulfate [V(max)/K(m) = 27.9 +/- 4.33 mu L/(min mg)] by human liver cytosol was less pronounced and is mediated by sulfotransferases 1A1* 1, 1A1* 2, 1A2, 1A3, 1B1, and 1E1. P450-mediated oxidation of honokiol by liver microsomes, however, was below detection limit. In summary, this study established that glucuronidation and sulfation are the main metabolic pathways for honokiol in rat and human liver, suggesting their major contribution to clearance in vivo. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3505-3516, 2011