Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles

Details

Serval ID
serval:BIB_298F67F18CA4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles
Journal
Journal of Pharmacology and Experimental Therapeutics
Author(s)
Roch-Ramel  F., Guisan  B., Diezi  J.
ISSN
0022-3565
Publication state
Published
Issued date
02/1997
Peer-reviewed
Oui
Volume
280
Number
2
Pages
839-45
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Feb
Abstract
Inhibition of [14C]-urate uptake by uricosuric and antiuricosuric agents was investigated in human brush-border membrane vesicles, urate being transported either by anion exchange mechanisms or by voltage sensitive pathway. The IC50 for drugs on [14C]-urate uptake in vesicles loaded with 1 mM cold urate or with 5 mM lactate was, respectively: 0.7 and 0.3 microM for benzbromarone; 6 and 4 microM for salicylate; 133 and 13 microM for losartan; 520 and 190 microM for sulfinpyrazone and 807 and 150 microM, for probenecid. The IC50 ratio for [14C]-urate uptake in exchange for cold urate or for lactate varied from about 1 for salicylate to 10 for losartan, supporting the hypothesis that two distinct anion exchangers are involved in urate transport. Application of Hill equation revealed that urate/anion exchangers have more than one binding site, possibly two binding sites with high cooperativity, for benzbromarone and sulfinpyrazone, but only one for probenecid, salicylate and losartan. The uricosuric diuretic, tienilic acid was 10 to 50 times more potent than hydrochlorothiazide, chlorothiazide and furosemide, for inhibiting [14C]-urate uptake in exchange for cold urate. This higher potency is the reason of its uricosuric properties. All uricosuric agents, as well as the antiuricosuric agents, pyrazinoate and ethambutol, had a much lower potency for inhibiting [14C]-urate uptake through the voltage sensitive pathway (apical secretory step) than through the urate/anion exchangers. This suggests that antiuricosuria, induced by pyrazinoate and ethambutol, as well as by low concentrations of uricosuric agents, does not result from an inhibition of the apical voltage sensitive pathway.
Keywords
Aged Benzbromarone/pharmacology Biological Transport/drug effects Biphenyl Compounds/pharmacology Carbon Radioisotopes Diuretics/*pharmacology Ethambutol/pharmacology Humans Imidazoles/pharmacology Kidney Cortex/*metabolism Kidney Neoplasms/metabolism Kinetics Losartan Microvilli/drug effects/*metabolism Middle Aged Probenecid/pharmacology Pyrazinamide/analogs & derivatives/pharmacology Salicylic Acid Salicylic Acids/pharmacology Sulfinpyrazone/pharmacology Tetrazoles/pharmacology Ticrynafen/pharmacology Uric Acid/*metabolism Uricosuric Agents/antagonists & inhibitors/*pharmacology
Pubmed
Web of science
Create date
21/01/2008 11:54
Last modification date
20/08/2019 13:09
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