Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4.
OBJECTIVE
The xanthine oxidase inhibitors allopurinol and oxypurinol are used to treat hyperuricaemia, whereas loop and thiazide diuretics can cause iatrogenic hyperuricaemia. Some uricosuric drugs and salicylate have a bimodal action on urate renal excretion. The mechanisms of action of these hypo- and hyperuricaemic drugs on the handling of urate in renal tubules have not been fully elucidated. Recently, we identified the multidrug resistance protein (MRP) 4 as a luminal efflux transporter for urate in the proximal tubule.


METHODS
Here, we studied the effect of these drugs on [(14)C]urate transport using human embryonic kidney 293 cells overexpressing human MRP4 and in membrane vesicles isolated from these cells.


RESULTS
Allopurinol stimulated MRP4-mediated cellular urate efflux and allopurinol and oxypurinol both markedly stimulated urate transport by MRP4 in membrane vesicles. Bumetanide and torasemide had no effect, whereas furosemide, chlorothiazide, hydrochlorothiazide, salicylate, benzbromarone and sulfinpyrazone inhibited urate transport, at concentrations ranging from nanomolar up to millimolar. Probenecid stimulated urate transport at 0.1 microM and inhibited transport at higher concentrations.


CONCLUSIONS
These data suggest that inhibition of MRP4-mediated urate efflux by furosemide and thiazide diuretics could have an important function in their hyperuricaemic mechanisms. Furthermore, stimulation of MRP4-mediated renal urate efflux could be a new mechanism in the hypouricaemic action of allopurinol and oxypurinol. In conclusion, MRP4 may provide a potential target for drugs affecting urate homoeostasis, which needs to be further evaluated in vivo.
El-Sheikh
A A K
AA
Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
van den Heuvel
J J M W
JJ
Koenderink
J B
JB
Russel
F G M
FG
D000493:Allopurinol / Q000008:administration & dosage / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000378:metabolism; D010117:Oxypurinol / Q000008:administration & dosage / Q000494:pharmacology; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology; D014527:Uric Acid / Q000378:metabolism*; D014528:Uricosuric Agents / Q000008:administration & dosage / Q000494:pharmacology*
D000493:Allopurinol; D004232:Diuretics; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010117:Oxypurinol; D012459:Salicylates; D014527:Uric Acid; D014528:Uricosuric Agents; C073492:ABCC4 protein, human