title: Interactions of fluoroquinolone antibacterials, DX-619 and levofloxacin, with creatinine transport by renal organic cation transporter hOCT2.
abstract: Interactions of DX-619, a novel fluoroquinolone antibacterial, and levofloxacin (LVFX) with the human renal organic cation transporter hOCT2 were studied. The intracellular accumulation of [(14)C]creatinine in stable transfectants of HEK293 cells expressing hOCT2 (hOCT2-HEK293) as well as vector-transfected HEK293 cells (VEC-HEK293) was evaluated in the presence of DX-619 and LVFX at various concentrations. When added extracellularly, both DX-619 and LVFX inhibited the uptake of [(14)C]creatinine (5 microM) by hOCT2-HEK293 cells in a dose-dependent manner. Unlike in hOCT2-HEK293 cells, the uptake in VEC-HEK293 cells was not inhibited by either fluoroquinolone suggesting that hOCT2 was specifically involved in the inhibition. The apparent IC(50) value for the inhibition of [(14)C]creatinine uptake in hOCT2-HEK293 cells was 1.29+/-0.23 microM for DX-619 and 127+/-27 microM for LVFX, indicating DX-619 to be approximately 100-fold more potent than LVFX at inhibiting the transport of [(14)C]creatinine by hOCT2. A Dixon plot revealed that the inhibition by DX-619 of the hOCT2-mediated transport of [(14)C]creatinine was competitive. Fluoroquinolone antibacterials have the ability to inhibit the transport of creatinine by hOCT2, with DX-619 being much more effective than LVFX.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okuda
authors.forename: Naoko
authors.initials: N
authors.lastname: Kimura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D002460:Cell Line; D003404:Creatinine / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D064704:Levofloxacin; D015394:Molecular Structure; D015242:Ofloxacin / Q000737:chemistry / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000502:physiology*; D000075102:Organic Cation Transporter 2; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D002250:Carbon Radioisotopes; C505440:DX 619; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011759:Pyrrolidines; D015363:Quinolones; C491013:SLC22A2 protein, human; D064704:Levofloxacin; D015242:Ofloxacin; D003404:Creatinine