Premium
Interaction of human Organic Anion Transporters with the loop diuretic torasemide and the impact on renal urate excretion
Author(s) -
Hagos Yohannes,
Bahn Andrew,
Vormfelde Stefan V.,
Brockmöller Jürgen,
Burckhardt Gerhard
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a909-d
Subject(s) - chemistry , organic anion transporter 1 , loop diuretic , pharmacology , reabsorption , renal physiology , pharmacokinetics , transporter , diuretic , biochemistry , renal function , sodium , biology , organic chemistry , gene
Torasemide, is currently the most efficient loop diuretic. It is metabolized in the liver to five different compounds. After active renal secretion torasemide inhibits reabsorption of sodium and chloride in the loop of Henle. It is not clear, which transport systems mediate the secretion of torasemide and its main metabolites M1, M3 and M5. In the present study, we demonstrate the interaction of torasemide and its metabolites M1, M3 and M5 with hOAT1, hOAT3 and hOAT4. [ 3 H] p ‐aminohippurate (PAH) uptake by hOAT1, and [ 3 H]estrone sulfate (ES) uptake by hOAT3 and hOAT4 were significantly inhibited. The affinity of each transporter to torasemide and its metabolites was determined by competitive inhibition studies. Dixon‐plots revealed K i values of 55.1, 124.6, 145.5 and 75.4 μM for hOAT1 for torasemide, M1, M3, and M5, respectively. hOAT3 exhibited similar affinities for torasemide, M1, M3 (≈89 μM), whereas the K i value for M5 was 59.5 μM. hOAT4 showed the highest affinity for torasemide and M3 with 45.0 μM and 54.7 μM, respectively, but a comparable affinity for M1 (107.2 μM). In contrast, hOAT4 did not show any interaction with M5. Preloading of hOAT‐expressing cells with torasemide and its metabolites resulted in a significant trans‐stimulation of PAH uptake by hOAT1 and ES uptake by hOAT3 and hOAT4. Our pharmacokinetic studies with 95 healthy subjects, which were treated with torasemide, showed after 3 to 4h a significant reduction of the fractional excretion of urate. The reason for this observation could be an inhibition of hOAT3‐mediated urate secretion at the basolateral side of the proximal tubule or/and a trans‐stimulation of urate reabsorption mediated by hOAT4 at the luminal side.