title: Organic anion transporter 3- and organic anion transporting polypeptides 1B1- and 1B3-mediated transport of catalposide.
abstract: We investigated the in vitro transport characteristics of catalposide in HEK293 cells overexpressing organic anion transporter 1 (OAT1), OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, organic cation transporter 1 (OCT1), OCT2, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). The transport mechanism of catalposide was investigated in HEK293 and LLC-PK1 cells overexpressing the relevant transporters. The uptake of catalposide was 319-, 13.6-, and 9.3-fold greater in HEK293 cells overexpressing OAT3, OATP1B1, and OATP1B3 transporters, respectively, than in HEK293 control cells. The increased uptake of catalposide via the OAT3, OATP1B1, and OATP1B3 transporters was decreased to basal levels in the presence of representative inhibitors such as probenecid, furosemide, and cimetidine (for OAT3) and cyclosporin A, gemfibrozil, and rifampin (for OATP1B1 and OATP1B3). The concentration-dependent OAT3-mediated uptake of catalposide revealed the following kinetic parameters: Michaelis constant (K m) =41.5 μM, maximum uptake rate (V max) =46.2 pmol/minute, and intrinsic clearance (CL int) =1.11 μL/minute. OATP1B1- and OATP1B3-mediated catalposide uptake also showed concentration dependency, with low CL int values of 0.035 and 0.034 μL/minute, respectively. However, the OCT1, OCT2, OAT1, P-gp, and BCRP transporters were apparently not involved in the uptake of catalposide into cells. In addition, catalposide inhibited the transport activities of OAT3, OATP1B1, and OATP1B3 with half-maximal inhibitory concentration values of 83, 200, and 235 μM, respectively. However, catalposide did not significantly inhibit the transport activities of OCT1, OCT2, OAT1, P-gp, or BCRP. In conclusion, OAT3, OATP1B1, and OATP1B3 are major transporters that may regulate the pharmacokinetic properties and may cause herb-drug interactions of catalposide, although their clinical relevance awaits further evaluation.
authors: College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea.
authors: Hyeon-Uk
authors: HU
authors: Jeong
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Korea.
authors: Mihwa
authors: M
authors: Kwon
authors: Central R&D Institute, Yungjin Pharm Co., Ltd., Suwon 443-270, Korea.
authors: Yongnam
authors: Y
authors: Lee
authors: Central R&D Institute, Yungjin Pharm Co., Ltd., Suwon 443-270, Korea.
authors: Ji Seok
authors: JS
authors: Yoo
authors: Central R&D Institute, Yungjin Pharm Co., Ltd., Suwon 443-270, Korea.
authors: Dae Hee
authors: DH
authors: Shin
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Korea.
authors: Im-Sook
authors: IS
authors: Song
authors: College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea.
authors: Hye Suk
authors: HS
authors: Lee
mesh_terms: D000818:Animals; D001692:Biological Transport; D004305:Dose-Response Relationship, Drug; D005960:Glucosides / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D041743:Herb-Drug Interactions; D006801:Humans; D007700:Kinetics; D018374:LLC-PK1 Cells; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine
chemical_list: D005960:Glucosides; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010936:Plant Extracts; C114338:organic anion transport protein 3; C006928:catalposide
keywords: OAT3; OATP1B1; OATP1B3; catalposide; drug transporters; herb–drug interaction
references: Curr Drug Metab. 2012 Jun 1;13(5):640-51
references: 22292789
references: Handb Exp Pharmacol. 2011;(201):299-323
references: 21103974
references: Pharmacol Rev. 2006 Jun;58(2):140-61
references: 16714484
references: Int Immunopharmacol. 2002 Jul;2(8):1173-81
references: 12349954
references: Cancer Res. 2006 Sep 1;66(17):8847-57
references: 16951202
references: Nat Rev Drug Discov. 2010 Mar;9(3):215-36
references: 20190787
references: Drug Metab Dispos. 2013 Mar;41(3):668-81
references: 23293300
references: Clin Pharmacol Ther. 2004 Oct;76(4):330-40
references: 15470332
references: J Ethnopharmacol. 2013 Jan 30;145(2):416-23
references: 23195129
references: Curr Med Chem. 2011;18(31):4836-50
references: 21919844
references: J Chem Biol. 2010 Mar;3(1):37-44
references: 19779939
references: J Pharmacol Sci. 2004 Feb;94(2):197-202
references: 14978359
references: Biochem Pharmacol. 2013 Oct 1;86(7):991-6
references: 23973525
references: Pharm Res. 2008 Aug;25(8):1807-14
references: 18236139
references: Inflamm Bowel Dis. 2004 Sep;10(5):564-72
references: 15472516
references: Am J Physiol Renal Physiol. 2006 Feb;290(2):F251-61
references: 16403838
references: Front Pharmacol. 2012 Apr 30;3:69
references: 22557968
references: Biopharm Drug Dispos. 2014 Apr;35(3):183-94
references: 24285344
references: FASEB J. 1997 Sep;11(11):835-41
references: 9285481
references: J Pharm Pharmacol. 2012 Aug;64(8):1074-83
references: 22775210
references: Hepatology. 2002 Jul;36(1):164-72
references: 12085361
references: Biochem Biophys Res Commun. 2012 Jun 15;422(4):568-72
references: 22583896
references: J Biochem Mol Toxicol. 2014 Feb;28(2):91-7
references: 24265111
references: Br J Pharmacol. 2009 Oct;158(3):693-705
references: 19785645
references: Pharm Biol. 2014 Dec;52(12):1510-7
references: 25026340
references: Toxicol Lett. 2003 Nov 1;145(1):46-54
references: 12962973
references: J Pharm Sci. 2013 Nov;102(11):4205-11
references: 24018852
references: J Pharm Sci. 2013 May;102(5):1683-7
references: 23457060
references: Gastroenterology. 2006 May;130(6):1793-806
references: 16697742
references: J Pharmacol Exp Ther. 2012 Mar;340(3):648-55
references: 22160269
references: Xenobiotica. 2010 Dec;40(12):817-25
references: 20863201
references: Planta Med. 2002 Aug;68(8):685-9
references: 12221588
references: Drug Metab Dispos. 2007 Aug;35(8):1308-14
references: 17470528
references: J Pharm Sci. 2012 May;101(5):1888-97
references: 22359351