Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1.
Article Details
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Uwai Y, Saito H, Hashimoto Y, Inui KI
Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1.
J Pharmacol Exp Ther. 2000 Oct;295(1):261-5.
- PubMed ID
- 10991988 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Acetazolamide Solute carrier family 22 member 6 Protein Humans UnknownInhibitorDetails Aminohippuric acid Solute carrier family 22 member 6 Protein Humans UnknownSubstrateInhibitorDetails Bumetanide Solute carrier family 22 member 6 Protein Humans UnknownSubstrateInhibitorDetails Chlorothiazide Solute carrier family 22 member 6 Protein Humans UnknownInhibitorDetails Cyclothiazide Solute carrier family 22 member 6 Protein Humans UnknownInhibitorDetails Ethoxzolamide Solute carrier family 22 member 6 Protein Humans UnknownInhibitorDetails Furosemide Solute carrier family 22 member 6 Protein Humans UnknownInhibitorInducerDetails Hydrochlorothiazide Solute carrier family 22 member 6 Protein Humans UnknownSubstrateInhibitorDetails Methazolamide Solute carrier family 22 member 6 Protein Humans UnknownInhibitorDetails