title: Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1.
abstract: 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-[(14)C]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 (K(i)) value was 1.1 mM for acetazolamide, 150 microM for hydrochlorothiazide, 9.5 microM for furosemide, and 5. 5 microM for bumetanide. Kinetic analysis revealed that acetazolamide inhibited rOAT1 competitively and that inhibition style of furosemide was a mixture of competitive and noncompetitive. [(14)C]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 [(14)C]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.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Uwai
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: K I
authors.initials: KI
authors.lastname: Inui
mesh_terms: D000086:Acetazolamide / Q000493:pharmacokinetics*; D000818:Animals; D027321:Anion Transport Proteins; D001692:Biological Transport; D002034:Bumetanide / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000502:physiology*; D004232:Diuretics / Q000493:pharmacokinetics*; D005665:Furosemide / Q000493:pharmacokinetics; D006852:Hydrochlorothiazide / Q000493:pharmacokinetics; D007684:Kidney Tubules / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics; D051381:Rats
chemical_list: D027321:Anion Transport Proteins; D002352:Carrier Proteins; D004232:Diuretics; D015609:Organotechnetium Compounds; C405303:technetium Tc 99m-aminohippuric acid; D006852:Hydrochlorothiazide; D002034:Bumetanide; D005665:Furosemide; D000086:Acetazolamide