RT Journal Article SR Electronic T1 Interaction and Transport of Thiazide Diuretics, Loop Diuretics, and Acetazolamide via Rat Renal Organic Anion Transporter rOAT1 JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 261 OP 265 VO 295 IS 1 A1 Yuichi Uwai A1 Hideyuki Saito A1 Yukiya Hashimoto A1 Ken-Ichi Inui YR 2000 UL http://jpet.aspetjournals.org/content/295/1/261.abstract AB The renal tubular secretion of thiazides and loop diuretics via the organic anion transport system in renal tubules is required for them to reach their principal sites of action. Similarly, acetazolamide, a diuretic clinically administered for glaucoma, is excreted from the kidney by glomerular filtration and tubular secretion. In this study, we investigated the interaction and transport of these diuretics via the rat renal organic anion transporter rOAT1 by using Xenopus laevis oocyte expression system.p-[14C]Aminohippurate (PAH) uptake by rOAT1-expressing oocytes was inhibited in the presence of a thiazide (chlorothiazide, cyclothiazide, hydrochlorothiazide), a loop diuretic (bumetanide, ethacrynic acid, furosemide), or a carbonic anhydrase inhibitor (acetazolamide, ethoxzolamide, methazolamide). Dixon plot analysis demonstrated that the inhibition constant (Ki) value was 1.1 mM for acetazolamide, 150 μM for hydrochlorothiazide, 9.5 μM for furosemide, and 5.5 μM for bumetanide. Kinetic analysis revealed that acetazolamide inhibited rOAT1 competitively and that inhibition style of furosemide was a mixture of competitive and noncompetitive. [14C]PAH efflux was significantly enhanced when the rOAT1-expressing oocytes were incubated in the presence of unlabeled PAH, α-ketoglutarate, acetazolamide, chlorothiazide, or hydrochlorothiazide. rOAT1 stimulated acetazolamide uptake, which was inhibited by probenecid. Although the loop diuretics had little trans-stimulation effect on [14C]PAH efflux via rOAT1, the rOAT1-mediated furosemide uptake was observed. These findings suggest that rOAT1 contributes, at least in part, to the renal tubular secretion of acetazolamide, thiazides, and loop diuretics. The American Society for Pharmacology and Experimental Therapeutics