title: Interactions of human organic anion transporters with diuretics.
abstract: The tubular secretion of diuretics in the proximal tubule has been shown to be critical for the action of drugs. To elucidate the molecular mechanisms for the tubular excretion of diuretics, we have elucidated the interactions of human organic anion transporters (hOATs) with diuretics using cells stably expressing hOATs. Diuretics tested were thiazides, including chlorothiazide, cyclothiazide, hydrochlorothiazide, and trichlormethiazide; loop diuretics, including bumetanide, ethacrynic acid, and furosemide; and carbonic anhydrase inhibitors, including acetazolamide and methazolamide. These diuretics inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4 in a competitive manner. hOAT1 exhibited the highest affinity interactions for thiazides, whereas hOAT3 did those for loop diuretics. hOAT1, hOAT3, and hOAT4 but not hOAT2, mediated the uptake of bumetanide. hOAT3 and hOAT4, but not hOAT1 mediated the efflux of bumetanide. hOAT1 and hOAT3, but not hOAT2 and hOAT4 mediated the uptake of furosemide. In conclusion, it was suggested that hOAT1 may play an important role in the basolateral uptake of thiazides, and hOAT3 in the uptake of loop diuretics. In addition, it was also suggested that bumetanide taken up by hOAT3 and/or hOAT1 is excreted into the urine by hOAT4.
authors: Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
authors: Habib
authors: H
authors: Hasannejad
authors: Michio
authors: M
authors: Takeda
authors: Kentarou
authors: K
authors: Taki
authors: Ho Jung
authors: HJ
authors: Shin
authors: Ellappan
authors: E
authors: Babu
authors: Promsuk
authors: P
authors: Jutabha
authors: Suparat
authors: S
authors: Khamdang
authors: Mahmoud
authors: M
authors: Aleboyeh
authors: Maristela Lika
authors: ML
authors: Onozato
authors: Akihiro
authors: A
authors: Tojo
authors: Atsushi
authors: A
authors: Enomoto
authors: Naohiko
authors: N
authors: Anzai
authors: Shinichi
authors: S
authors: Narikawa
authors: Xiu-Lin
authors: XL
authors: Huang
authors: Toshimitsu
authors: T
authors: Niwa
authors: Hitoshi
authors: H
authors: Endou
mesh_terms: D000818:Animals; D001692:Biological Transport; D002034:Bumetanide / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004232:Diuretics / Q000493:pharmacokinetics*; D005665:Furosemide / Q000032:analysis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D027361:Organic Anion Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D004232:Diuretics; D027361:Organic Anion Transporters; D002034:Bumetanide; D005665:Furosemide