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Vol. 295, Issue 1, 261-265, October 2000

Interaction and Transport of Thiazide Diuretics, Loop Diuretics, and Acetazolamide via Rat Renal Organic Anion Transporter rOAT11

Yuichi Uwai, Hideyuki Saito, Yukiya Hashimoto and Ken-Ichi Inui

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan

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, alpha -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.

1 This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan; a grant from the Yamanouchi Foundation for Research on Metabolic Disorders; and a grant from the Uehara Memorial Foundation.

0022-3565/00/2951-0261$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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