title: Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone.
abstract: 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 K(m) of about 800 microM. Moreover, benzbromarone inhibited the oxypurinol uptake by URAT1 at concentrations as low as 0.01 microM. 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwanaga
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirayama
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001553:Benzbromarone / Q000494:pharmacology*; D002352:Carrier Proteins / Q000502:physiology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D027361:Organic Anion Transporters / Q000502:physiology*; D027701:Organic Cation Transport Proteins / Q000502:physiology; D010117:Oxypurinol / Q000493:pharmacokinetics*; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D014527:Uric Acid / Q000494:pharmacology; D014528:Uricosuric Agents / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D014528:Uricosuric Agents; D014527:Uric Acid; D001553:Benzbromarone; D010117:Oxypurinol