Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Drug Metab Dispos. 2011 Apr;39(4):667-74. doi: 10.1124/dmd.110.037333. Epub 2011 Jan 5.
Luteolin is mainly metabolized by phase II enzymes in animals and humans with glucuronidation and sulfation as the two known metabolic pathways. Although methylation of luteolin was reported previously, the structure of the methylated metabolites and the enzymes involved in the process have not been clarified. In our study, two methylated metabolites, M1 (chrysoeriol) and M2 (diosmetin), were identified in the urine after intravenous administration of luteolin to rats, and the data suggested that the methylation was mediated by catechol-O-methyltransferase (COMT). When luteolin was coadministered with a specific COMT inhibitor, entacapone, the formation of M1 and M2 was significantly reduced, whereas the plasma concentration of luteolin increased. Methylation of luteolin was also studied in vitro using rat tissue homogenates. The apparent kinetic parameters associated with the formation of M1 and M2 in vitro were estimated, and regioselectivity of methylation of luteolin was observed. In the in vitro experiment, there was a preference for the formation of M2 over M1. In contrast, accumulation of M1 was preferred in vivo in both rat plasma and urine after an intravenous dose of luteolin. In conclusion, COMT played a crucial role in the disposition of luteolin in rats. Our results indicated that the methylation pathway in rats was significantly reduced when luteolin was coadministered with a specific COMT inhibitor. Therefore, COMT-associated drug-drug interactions need be considered in the future in luteolin clinical trials because the plasma concentrations and related therapeutic effects may be altered in vivo in the presence of a COMT inhibitor.
木樨草素主要在动物和人体内通过葡萄糖醛酸化和硫酸化作为两种已知的代谢途径被 II 相酶代谢。虽然以前曾报道过木樨草素的甲基化，但尚未阐明甲基化代谢产物的结构以及参与该过程的酶。在我们的研究中，静脉给予大鼠木樨草素后，在尿液中鉴定出两种甲基化代谢产物 M1（芹菜素）和 M2（圣草酚），并且数据表明该甲基化是由儿茶酚-O-甲基转移酶（COMT）介导的。当木樨草素与特定的 COMT 抑制剂恩他卡朋共同给予时，M1 和 M2 的形成明显减少，而木樨草素的血浆浓度增加。还使用大鼠组织匀浆在体外研究了木樨草素的甲基化。体外测定了形成 M1 和 M2 的表观动力学参数，并观察到木樨草素的甲基化的区域选择性。在体外实验中，观察到 M2 的形成优先于 M1。相反，静脉给予木樨草素后，无论是在大鼠血浆还是尿液中，M1 的积累在体内都优先于 M2。总之，COMT 在大鼠中木樨草素的处置中起着至关重要的作用。我们的结果表明，当木樨草素与特定的 COMT 抑制剂共同给予时，大鼠中的甲基化途径明显减少。因此，在未来的木樨草素临床试验中需要考虑 COMT 相关的药物相互作用，因为在存在 COMT 抑制剂的情况下，体内的血浆浓度和相关治疗效果可能会发生改变。
