Vol. 303, No. 2 37580/1014526 Printed in U.S.A.
Interactions of Human Organic Anion Transporters and Human Organic Cation Transporters with Nonsteroidal AntiInflammatory Drugs
SUPARAT KHAMDANG, MICHIO TAKEDA, RIE NOSHIRO, SHINICHI NARIKAWA, ATSUSHI ENOMOTO, NAOHIKO ANZAI, PAWINEE PIYACHATURAWAT, and HITOSHI ENDOU
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan (S.K., M.T., R.N., S.N., A.E., N.A., H.E.); and Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand (S.K., P.P.) Received April 15, 2002; accepted July 9, 2002
ABSTRACT The purpose of this study was to elucidate the interactions of human organic anion transporters (hOATs) and human organic cation transporters (hOCTs) with nonsteroidal anti-inflammatory drugs (NSAIDs) using cells stably expressing hOATs and hOCTs. NSAIDs tested were acetaminophen, acetylsalicylate, salicylate, diclofenac, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, piroxicam, phenacetin, and sulindac. These NSAIDs inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4. By comparing the IC50 values of NSAIDs for hOATs, it was found that hOAT1 and hOAT3 exhibited higher affinity interactions with NSAIDs than
did hOAT2 and hOAT4. HOAT1, hOAT2, hOAT3, and hOAT4 mediated the uptake of either ibuprofen, indomethacin, ketoprofen, or salicylate, but not acetylsalicylate. Although organic cation uptake mediated by hOCT1 and hOCT2 was also inhibited by some NSAIDs, hOCT1 and hOCT2 did not mediate the uptake of NSAIDs. In conclusion, hOATs and hOCTs interacted with various NSAIDs, whereas hOATs but not hOCTs mediated the transport of some of these NSAIDs. Considering the localization of hOATs, it was suggested that the interactions of
References: Abe T, Kakyo M, Sakagami H, Tokui T, Nishio T, Tanemoto M, Nomura H, Hebert SC, Matsuno S, Kondo H, et al. (1998) Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J Biol Chem 273:22395–22401. Apiwattanakul N, Sekine T, Chairoungdua A, Kanai Y, Nakajima N, Sophasan S, and Endou H (1999) Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes. Mol Pharmacol 55:847– 854. Babu E, Takeda M, Narikawa S, Kobayashi Y, Enomoto A, Tojo A, Cha SH, Sekine T, Sakthisekaran D, and Endou H (2002) Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim Biophys Acta 1590:64 –75. Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt P, Ulzheimer JC, Sonders MS, Baumann C, et al. (1998) Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine and memantine. Mol Pharmacol 54:342–352. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, and Endou H (2001) Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol 59:1277–1286. Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, and Endou H (2000) Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem 275:4507– 4512. Chan LY, Chiu PY, Siu SS, and Lau TK (2001) A study of diclofenac-induced teratogenicity during organogenesis using a whole rat embryo culture model. Hum Reprod (Oxf) 16:2390 –2393. Cheng YC and Prusoff WH (1973) Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 22:3099 –3108. Day R, Quinn D, Williams K, Handel M, and Brooks P (2000) Connective tissue and bone disorders, in Clinical Pharmacology (Carruthers SG, Hoffmann BB, Melmon KL, and Nierenberg DW eds) pp 645–702, McGraw-Hill, New York. Delrio FG, Park Y, Herzlich B, and Grob D (1996) Case report: diclofenac-induced rhabdomyolysis. Am J Med Sci 312:95–97. Enomoto A, Takeda M, Shimoda M, Narikawa S, Kobayashi Y, Kobayashi Y, Yamamoto T, Sekine T, Cha SH, Niwa T, and Endou H (2002) Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J Pharmacol Exp Ther 301:797– 802. Ferrier B, Martin M, and Roch-Ramel F (1983) Effects of p-aminohippurate and pyrazinoate on the renal excretion of salicylate in the rat: a micropuncture study. J Pharmacol Exp Ther 224:451– 458. Frust DE and Munster T (2000) Nonsteroidal anti-inflammatory drugs, diseasemodifying antirheumatic drugs, nonopioid analgesics, & drugs used in gout, in Basic & Clinical Pharmacology, 8th ed (Katzung BG ed) pp 596 – 616, McGrawHill, New York. Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, and Koepsell H (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871– 881. Hoppman RA, Peden JG, and Ober SK (1991) Central nervous system side effects of nonsteroidal anti-inflammatory drugs. Arch Intern Med 151:1309 –1313. Hosoyamada M, Sekine T, Kanai Y, and Endou H (1999) Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol 276:F122–F128. Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, and Meier PJ (1994) Expression cloning of a rat liver Na -independent organic anion transporter. Proc Natl Acad Sci USA 91:133–137. Janssen NM and Genta MS (2000) The effects of immunosuppressive and antiinflammatory medications on fertility, pregnancy and lactation. Arch Intern Med 160:610 – 619. Kimmel CA, Wilson JG, and Schumacher HJ (1971) Studies on metabolism and identification of the causative agent in aspirin teratogenesis in rats. Teratology 4:15–24. Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, and Endou H (2002) Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther 301:293–298. Leier I, Hummel-Eisenbeiss J, Cui Y, and Keppler D (2000) ATP-dependent paraaminohippurate transport by apical multidrug resistance protein MRP2. Kidney Int 57:1636 –1642. Leventhal LJ, Kuritsky L, Ginsburg R, and Bomalaski JS (1989) Salicylate-induced rhabdomyolysis. Am J Emerg Med 7:409 – 410. Masuda S, Ibaramoto K, Takeuchi A, Saito H, Hashimoto Y, and Inui KI (1999) Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney. Mol Pharmacol 55:743–752. Morita N, Kusuhara H, Sekine T, Endou H, and Sugiyama Y (2001) Functional characterization of rat organic anion transporter 2 in LLC-PK1 cells. J Pharmacol Exp Ther 298:1179 –1184. Noe B, Hagenbuch B, Stieger B, and Meier PJ (1997) Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci USA 94:10346 –10350. Pritchard JB and Miller DS (1993) Mechanisms mediating renal secretion of organic anions and cations. Physiol Rev 73:765–796. Purcell P, Henry D, and Melville G (1991) Diclofenac hepatitis. Gut 32:1381–1385. Reid G, Wolff NA, Dautzenberg FM, and Burckhardt G (1998) Cloning of a human renal p-aminohippurate transporter, hROAT1. Kidney Blood Press Res 121:233–237. Robertson CE, Ford MJ, Van Someren V, Dlugolecka M, and Prescott LF (1980) Mefenamic acid nephropathy. Lancet 2:232–233. Ross NS and Hoppel CL (1987) Partial muscle carnitine palmitoyltransferase-A deficiency. Rhabdomyolysis associated with transiently decreased muscle carnitine content after ibuprofen therapy. J Am Med Assoc 257:62– 65. Saito H, Masuda S, and Inui KI (1996) Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kidney. J Biol Chem 271:20719 –20725. Schild L and Roch-Ramel F (1988) Transport of salicylate in proximal tubule (S2 segment) isolated from rabbit kidney. Am J Physiol 254:F554 –F561. Shah GM, Muhalwas KK, and Winer RL (1981) Renal papillary necrosis due to ibuprofen. Arthritis Rheum 24:1208 –1210. Takeda M, Babu E, Narikawa S, and Endou H (2002) Interaction of human organic anion transporters with various cephalosporin antibiotics. Eur J Pharmacol 438: 137–142. Uchino H, Tamai I, Yamashita K, Minemoto Y, Sai Y, Yabuuchi H, Miyamoto K, Takeda E, and Tsuji A (2000) p-Aminohippuric acid transport at renal apical membrane mediated by human inorganic phosphate transporter NPT1. Biochem Biophys Res Commun 270:254 –259. Uwai Y, Saito H, and Inui K (2000) Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter. Eur J Pharmacol 409:31–36. Wood LJ, Mundo F, Searle J, and Powell LW (1985) Sulindac hepatotoxicity: effects of acute and chronic exposure. Aust NZ J Med 15:397– 401. Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway SJ, Leibach FH, and Ganapathy V (2000) Structure, function and regional distribution of the organic cation transporter OCT3 in the kidney. Am J Physiol Renal Physiol 279:F449–F458. Zhang L, Schaner ME, and Giacomini KM (1998) Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther 286:354 –361. Zimmerman HJ (1981) Effects of aspirin and acetaminophen on the liver. Arch Intern Med 141:333–342. Address correspondence to: Dr. Hitoshi Endou, Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan. E-mail: firstname.lastname@example.org