title: Characteristics of pemetrexed transport by renal basolateral organic anion transporter hOAT3.
abstract: OBJECTIVE
  Pemetrexed transport by human organic anion transporters, hOAT1 (SLC22A6) and hOAT3 (SLC22A8), were characterized in comparison with methotrexate.
  
  
  METHODS
  Accumulation of pemetrexed and methotrexate in hOAT1- and hOAT3-expressing cells were evaluated. Pemetrexed and methotrexate were determined by HPLC. Kinetic parameters were calculated by Eadie-Hofstee plot.
  
  
  RESULTS
  When HEK-hOAT3 and -hOAT1 cells were incubated with 100 µM pemetrexed for 30 min, pemetrexed was accumulated at 14- and 1.7-fold greater than that in control cells, respectively. Pemetrexed and methotrexate transport by hOAT3 was saturated at high concentrations with apparent Km values 28.2 µM and 76.6 µM, respectively. In addition, intrinsic activity (Vmax/Km) of pemetrexed and methotrexate transport by hOAT3 was 4.82 and 0.42 µl/min/mg protein, respectively, suggesting 11-fold higher transport of pemetrexed than methotrexate by hOAT3. Furthermore, loxoprofen, ibuprofen, pravastatin, and cefazolin, transport substrates of hOAT3, inhibited pemetrexed transport by hOAT3 with IC50 values, 34.2, 27.9, 76.3 and 650 µM, respectively.
  
  
  CONCLUSIONS
  Pemetrexed is a superior substrate to methotrexate for hOAT3. Loxoprofen, ibuprofen, and cefazolin could cause drug-drug interactions when attaining high blood concentrations.
authors.affiliation: Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kurata
authors.forename: Takuya
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawahara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okuda
mesh_terms: D001692:Biological Transport; D004347:Drug Interactions; D005493:Folic Acid Antagonists / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008727:Methotrexate / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000068437:Pemetrexed; D014162:Transfection
chemical_list: D005493:Folic Acid Antagonists; D005971:Glutamates; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D000068437:Pemetrexed; D006147:Guanine; D008727:Methotrexate