RT Journal Article
SR Electronic
T1 INVOLVEMENT OF URIC ACID TRANSPORTER IN INCREASED RENAL CLEARANCE OF THE XANTHINE OXIDASE INHIBITOR OXYPURINOL INDUCED BY A URICOSURIC AGENT, BENZBROMARONE
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1791
OP 1795
DO 10.1124/dmd.105.006056
VO 33
IS 12
A1 Takashi Iwanaga
A1 Daisuke Kobayashi
A1 Masamichi Hirayama
A1 Tomoji Maeda
A1 Ikumi Tamai
YR 2005
UL http://dmd.aspetjournals.org/content/33/12/1791.abstract
AB Benzbromarone has been reported to increase the renal clearance of oxypurinol, an active metabolite of allopurinol. We examined the renal transport of oxypurinol to determine whether such a change in renal clearance could be explained by altered transporter-mediated reabsorption. Since the first step of reabsorption takes place at the renal epithelial apical membrane, we focused on membrane transporters. Benzbromarone is an inhibitor of reabsorption of uric acid mediated by the uric acid transporter (URAT) URAT1 (SLC22A12), which is expressed at the apical membrane of proximal tubular cells in humans. Uptake of oxypurinol by Xenopus oocytes injected with complementary RNA of URAT1 was significantly higher than that by water-injected oocytes, and the uptake was saturable, with a Km of about 800 μM. Moreover, benzbromarone inhibited the oxypurinol uptake by URAT1 at concentrations as low as 0.01 μM. The uptake of oxypurinol by another organic anion transporter (OAT), OAT4 (SLC22A11), which is also expressed at the apical membrane of proximal tubular epithelial cells, was negligible, whereas the uptake of [3H]estrone-3-sulfate by OAT4 was significantly inhibited by oxypurinol. Furthermore, neither the transport activity of organic cation/carnitine transporter (OCTN) 1 nor OCTN2 was affected by oxypurinol or benzbromarone. These results indicate that URAT1 is involved in renal reabsorption of oxypurinol, and the increment of renal clearance of oxypurinol upon concomitant administration of benzbromarone could be due to drug interaction at URAT1. The American Society for Pharmacology and Experimental Therapeutics