Tags

Type your tag names separated by a space and hit enter

Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone.
Drug Metab Dispos. 2005 Dec; 33(12):1791-5.DM

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+Show Affiliations

Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16135657

Citation

Iwanaga, Takashi, et al. "Involvement of Uric Acid Transporter in Increased Renal Clearance of the Xanthine Oxidase Inhibitor Oxypurinol Induced By a Uricosuric Agent, Benzbromarone." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 33, no. 12, 2005, pp. 1791-5.
Iwanaga T, Kobayashi D, Hirayama M, et al. Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. Drug Metab Dispos. 2005;33(12):1791-5.
Iwanaga, T., Kobayashi, D., Hirayama, M., Maeda, T., & Tamai, I. (2005). Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 33(12), 1791-5.
Iwanaga T, et al. Involvement of Uric Acid Transporter in Increased Renal Clearance of the Xanthine Oxidase Inhibitor Oxypurinol Induced By a Uricosuric Agent, Benzbromarone. Drug Metab Dispos. 2005;33(12):1791-5. PubMed PMID: 16135657.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. AU - Iwanaga,Takashi, AU - Kobayashi,Daisuke, AU - Hirayama,Masamichi, AU - Maeda,Tomoji, AU - Tamai,Ikumi, Y1 - 2005/08/31/ PY - 2005/9/2/pubmed PY - 2005/12/29/medline PY - 2005/9/2/entrez SP - 1791 EP - 5 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 33 IS - 12 N2 - 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/16135657/Involvement_of_uric_acid_transporter_in_increased_renal_clearance_of_the_xanthine_oxidase_inhibitor_oxypurinol_induced_by_a_uricosuric_agent_benzbromarone_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16135657 DB - PRIME DP - Unbound Medicine ER -