TY - JOUR T1 - Interactions of Human Organic Anion Transporters with Diuretics JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1021 LP - 1029 DO - 10.1124/jpet.103.059139 VL - 308 IS - 3 AU - Habib Hasannejad AU - Michio Takeda AU - Kentarou Taki AU - Ho Jung Shin AU - Ellappan Babu AU - Promsuk Jutabha AU - Suparat Khamdang AU - Mahmoud Aleboyeh AU - Maristela Lika Onozato AU - Akihiro Tojo AU - Atsushi Enomoto AU - Naohiko Anzai AU - Shinichi Narikawa AU - Xiu-Lin Huang AU - Toshimitsu Niwa AU - Hitoshi Endou Y1 - 2004/03/01 UR - http://jpet.aspetjournals.org/content/308/3/1021.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -