Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Drug Metab Dispos. 2012 Oct;40(10):2009-20. doi: 10.1124/dmd.112.047183. Epub 2012 Jul 20.
Scutellarin [scutellarein-7-O-glucuronide (S-7-G)] displayed a unique pharmacokinetic profile in humans after oral administration: the original compound was hardly detected, whereas its isomeric metabolite isoscutellarin [scutellarein-6-O-glucuronide (S-6-G)] had a markedly high exposure. Previous rat study revealed that S-7-G and S-6-G in the blood mainly originated from their aglycone in enterocytes, and that the S-7-G/S-6-G ratio declined dramatically because of a higher hepatic elimination of S-7-G. In the present study, metabolite profiling in human excreta demonstrated that the major metabolic pathway for S-6-G and S-7-G was through further glucuronidation. To further understand the cause for the exposure difference between S-7-G and S-6-G in humans, studies were conducted to uncover mechanisms underlying their formation and elimination. In vitro metabolism study suggested that S-7-G was formed more easily but metabolized more slowly in human intestinal and hepatic microsomes. Efflux transporter study showed that S-6-G and S-7-G were good substrates of breast cancer resistance protein and multidrug resistance-associated protein (MRP) 2 and possible substrates of MRP3; however, there was no preference great enough to alter the S-7-G/S-6-G ratio in the blood. Among the major hepatic anion uptake transporters, organic anion-transporting polypeptide (OATP) 2B1 played a predominant role in the hepatic uptake of S-6-G and S-7-G and showed greater preference for S-7-G with higher affinity than S-6-G (K(m) values were 1.77 and 43.9 μM, respectively). Considering the low intrinsic permeability of S-6-G and S-7-G and the role of OATP2B1 in the hepatic clearance of such compounds, the selective hepatic uptake of S-7-G mediated by OATP2B1 is likely a key determinant for the much lower systemic exposure of S-7-G than S-6-G in humans.
灯盏乙素苷（scutellarein-7-O-葡萄糖醛酸苷，S-7-G）在人体口服后呈现出独特的药代动力学特征：原化合物几乎检测不到，而其同分异构体异灯盏乙素苷（scutellarein-6-O-葡萄糖醛酸苷，S-6-G）则具有明显的高暴露量。先前的大鼠研究表明，血液中的 S-7-G 和 S-6-G 主要来源于肠细胞中的苷元，并且由于 S-7-G 的肝消除率较高，S-7-G/S-6-G 比值急剧下降。在本研究中，人排泄物中的代谢物分析表明，S-6-G 和 S-7-G 的主要代谢途径是通过进一步的葡萄糖醛酸化。为了进一步了解 S-7-G 和 S-6-G 在人体中暴露差异的原因，进行了研究以揭示其形成和消除的机制。体外代谢研究表明，S-7-G 在人肠和肝微粒体中更容易形成但代谢更慢。外排转运体研究表明，S-6-G 和 S-7-G 是乳腺癌耐药蛋白和多药耐药相关蛋白 2（MRP2）的良好底物，可能也是多药耐药相关蛋白 3（MRP3）的底物；然而，没有足够的偏好性来改变血液中的 S-7-G/S-6-G 比值。在主要的肝阴离子摄取转运体中，有机阴离子转运多肽（OATP）2B1 在 S-6-G 和 S-7-G 的肝摄取中起主要作用，并且对 S-7-G 的亲和力比对 S-6-G 更高（K(m) 值分别为 1.77 和 43.9 μM）。考虑到 S-6-G 和 S-7-G 的内在通透性较低以及 OATP2B1 在这些化合物的肝清除中的作用，OATP2B1 介导的 S-7-G 的选择性肝摄取可能是 S-7-G 系统暴露量远低于 S-6-G 的关键决定因素。
