title: Identification of Transporters Involved in Beraprost Sodium Transport In Vitro.
abstract: OBJECTIVE
  Beraprost sodium (BPS) is a chemically stable and orally active prostacyclin analog that is used in the treatment of chronic arterial occlusive disease since 1992 and primary pulmonary hypertension since 1999 in Japan. Multiple-drug therapy is common in clinical practice, and BPS is co-administered with other drugs. Membrane transporters are known to markedly affect pharmacokinetics, safety and efficacy, and many transporter-based drug-drug interactions have been recently reported. However, information on the transporters involved in the pharmacokinetics of BPS is limited.
  
  
  METHODS
  First of all, we have examined 11 transporters, ABCB1 (P-glycoprotein: P-gp), ABCG2 (breast cancer resistance protein: BCRP), SLC22A6 (organic anion transporter 1: OAT1), SLC22A8 (organic anion transporter 3: OAT3), SLCO1B1 (organic anion transporting polypeptide 1B1: OATP1B1), SLCO1B3 (organic anion transporting polypeptide 1B3: OATP1B3), SLCO2B1 (organic anion transporting polypeptide 2B1: OATP2B1), SLC22A1 (organic cation transporter 1: OCT1), SLC22A2 (organic cation transporter 2: OCT2), ABCB11 (bile-salt export pump: BSEP), and ABCC2 (multidrug resistance associated protein 2: MRP2) to clarify which of them would be candidates that might recognize BPS as their substrate in transporter-expressing LLC-PK1, S2, and HEK293 cells as well as in membrane vesicles. Furthermore, we determined whether the transport of BPS was inhibited by the typical inhibitors of each transporter, i.e., verapamil for P-gp, Ko143 for BCRP, probenecid for OAT3, rifampicin for OATP1B1 and OATP1B3, cyclosporine for BSEP, and sulfobromophthalein (BSP) for MRP2.
  
  
  RESULTS
  The results obtained showed that P-gp, BCRP, OAT3, OATP1B1, OATP1B3, BSEP and MRP2 might be candidates for BPS transporters. From the further evaluation with the typical inhibitors of each transporter, it was confirmed that BPS is a substrate for P-gp, BCRP, OAT3, OATP1B1, OATP1B3 and MRP2, because the typical inhibitor, cyclosporine, had no effects on BPS transport by BSEP.
  
  
  CONCLUSIONS
  BPS is a substrate of 6 transporters: P-gp, BCRP, OAT3, OATP1B1, OATP1B3, and MRP2, because their expressing cells and vesicles transported BPS more than in the controls, and BPS transport activities were reduced by the typical inhibitors of tested transporters. Although there are no reports regarding drug-drug interactions between BPS and possible combination drugs expected due to transporters, it may be necessary to notice that that substrates or inhibitors for the 6 mentioned transporters may have effects on pharmacokinetics of BPS when co-administered.
authors.affiliation: Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1, Tebiro 6-chome, Kamakura, Kanagawa, 248-8555, Japan.
authors.forename: Keiyu
authors.initials: K
authors.lastname: Oshida
authors.affiliation: Pharmaceutical Clinical Research Department, Toray Industries, Inc., 1-1, Nihonbashi-muromachi 2-chome, Chuo-ku, Tokyo, 103-8666, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shimamura
authors.affiliation: ADME & Tox. Research Institute, Sekisui Medical Co., Ltd., 2117 Muramatsu, Tokai-mura, Naka-gun, Ibaraki, 319-1182, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Seya
authors.affiliation: Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1, Tebiro 6-chome, Kamakura, Kanagawa, 248-8555, Japan.|Pharmaceutical Clinical Research Department, Toray Industries, Inc., 1-1, Nihonbashi-muromachi 2-chome, Chuo-ku, Tokyo, 103-8666, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ando
authors.affiliation: Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1, Tebiro 6-chome, Kamakura, Kanagawa, 248-8555, Japan. Youhei_Miyamoto@nts.toray.co.jp.|Pharmaceutical Clinical Research Department, Toray Industries, Inc., 1-1, Nihonbashi-muromachi 2-chome, Chuo-ku, Tokyo, 103-8666, Japan. Youhei_Miyamoto@nts.toray.co.jp.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D004347:Drug Interactions; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D013552:Swine
chemical_list: C000715087:ABCC2 protein, human; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; C048081:beraprost; D011464:Epoprostenol