title: Absorption and disposition of scutellarin in rats: a pharmacokinetic explanation for the high exposure of its isomeric metabolite.
abstract: Scutellarin or scutellarein-7-O-glucuronide (S-7-G) is a flavonoid used in the treatment of cardiovascular diseases. After oral administration to humans, S-7-G can hardly be detected, whereas its isomeric metabolite [scutellarein-6-O-glucuronide (S-6-G)] dominates in plasma. A preliminary study in rats also revealed a low bioavailability of S-7-G, as well as a high plasma concentration of S-6-G. Therefore, the present study tried to explore the possible causes of the unusual pharmacokinetics of scutellarin in humans through investigating the absorption and disposition of S-7-G in rats. After oral administration to rats, S-7-G was largely hydrolyzed in the intestinal tract and was absorbed as aglycone. While passing through the intestinal wall, aglycone was extensively glucuronidated into S-7-G and S-6-G (approximately 20:1), which subsequently entered the mesenteric blood (approximately 15:1). However, because S-7-G exhibited more rapid uptake in hepatocytes, was glucuronidated at a 2.7-fold higher rate in the liver, and was excreted in greater amounts through bile and urine than S-6-G, the S-7-G/S-6-G ratio eventually declined to approximately 1.5:1 in the systemic circulation. Findings revealed that S-7-G cannot be absorbed directly; S-7-G and S-6-G in the body were mostly generated from aglycone in the intestinal wall; a larger amount of S-7-G than S-6-G entered the mesenteric blood at the absorption stage, but the gap between them shrank quickly mainly because of the higher hepatic first-pass elimination of S-7-G. These findings in rats are of great value as reference for further study to accurately interpret the pharmacokinetics of S-7-G in humans.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Gao
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D047310:Apigenin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation
chemical_list: D005965:Glucuronates; D020719:Glucuronides; C484876:scutellarin; D047310:Apigenin