title: Mechanistic studies on the absorption and disposition of scutellarin in humans: selective OATP2B1-mediated hepatic uptake is a likely key determinant for its unique pharmacokinetic characteristics.
abstract: 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.
authors: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Chunying
authors: C
authors: Gao
authors: Hongjian
authors: H
authors: Zhang
authors: Zitao
authors: Z
authors: Guo
authors: Tiangeng
authors: T
authors: You
authors: Xiaoyan
authors: X
authors: Chen
authors: Dafang
authors: D
authors: Zhong
mesh_terms: D000284:Administration, Oral; D000328:Adult; D047310:Apigenin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D047309:Flavones / Q000493:pharmacokinetics; D005965:Glucuronates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D055432:Metabolomics / Q000379:methods; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D014162:Transfection
chemical_list: C000715087:ABCC2 protein, human; D004365:Drugs, Chinese Herbal; D047309:Flavones; D005965:Glucuronates; D020719:Glucuronides; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; C484876:scutellarin; C000722867:isoscutellarein; D047310:Apigenin; D014453:Glucuronosyltransferase