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 hOATs with NSAIDs are associated with the pharmacokinetics and the induction of adverse reactions of NSAIDs.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used for their anti-inflammatory and analgesic properties. The indications of NSAIDs are broadening from rheumatic diseases and various pain states, such as cancer pain, and biliary and colic pain, to include possibly Alzheimer’s disease and colon cancer prevention (Day et al., 2000). Table 1 shows the chemical structures of NSAIDs tested in the current study. Although all of these NSAIDs are weak organic acids, they are grouped in several classes based on their chemical structures. Although the chemical diversity yields a broad range of pharmacokinetic characteristics (Frust and Munster, 2000), they have some general properties in common. NSAIDs have been shown to induce various forms of adverse drug reactions including adverse gastrointestinal effects (Day et al., 2000), renal dysfunction and nephrotoxicity (Day et al., 2000), liver damage (Zimmerman, Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.037580.
1981; Wood et al., 1985; Purcell et al., 1991; Day et al., 2000), adverse neurological effects (Hoppman et al., 1991; Day et al., 2000), and rhabdomyolysis (Ross and Hoppel, 1987; Leventhal et al., 1989; Delrio et al., 1996). The secretion of numerous organic anions and cations, including endogenous metabolites, drugs, and xenobiotics, is an important physiological function of the renal proximal tubule. The process of secreting organic anions and cations through the proximal tubule cells is achieved via unidirectional transcellular transport involving the uptake of organic anions and cations into the cells from the blood across the basolateral membrane, followed by extrusion across the brush-border membrane into the proximal tubule fluid (Pritchard and Miller, 1993). Recently, cDNAs encoding the human...