TY - JOUR T1 - FUNCTIONAL INVOLVEMENT OF RAT ORGANIC ANION TRANSPORTER 2 (<em>SLC22A7</em>) IN THE HEPATIC UPTAKE OF THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG KETOPROFEN JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1151 LP - 1157 DO - 10.1124/dmd.104.001552 VL - 33 IS - 8 AU - Naomi Morita AU - Hiroyuki Kusuhara AU - Yoshitane Nozaki AU - Hitoshi Endou AU - Yuichi Sugiyama Y1 - 2005/08/01 UR - http://dmd.aspetjournals.org/content/33/8/1151.abstract N2 - Rat organic anion transporter 2 (rOat2, Slc22a7) is a sinusoidal multispecific organic anion transporter in the liver. The role of rOat2 in the hepatic uptake of drugs has not been thoroughly investigated yet. rOat2 substrates include nonsteroidal anti-inflammatory drugs, such as ketoprofen, indomethacin, and salicylate. In the present study, the uptake of ketoprofen, indomethacin, and salicylate by freshly isolated rat hepatocytes was characterized. The uptake of ketoprofen, indomethacin, and salicylate by hepatocytes was sodium-independent, and the rank order of their uptake activities was indomethacin &gt; ketoprofen &gt; salicylate. Kinetic analysis based on Akaike's Information Criterion suggested that the uptake of ketoprofen and indomethacin by hepatocytes consists of two saturable components and one nonsaturable one. The Km and Vmax values for the high- and low-affinity components for ketoprofen uptake were 0.84 and 97 μM and 35 and 1800 pmol/min/mg protein, respectively, whereas those for indomethacin were 1.1 and 140 μM and 130 and 16,000 pmol/min/mg protein, respectively. The Km values of the high-affinity component were similar to those for rOat2 (3.3 and 0.37 μM for ketoprofen and indomethacin, respectively). The uptake of ketoprofen by hepatocytes was significantly inhibited by probenecid and rOat2 inhibitors (indocyanine green, indomethacin, glibenclamide, and salicylate). Other inhibitors of rOatps (taurocholate and pravastatin) and rOat3 (pravastatin and p-aminohippurate) had a slight effect, but digoxin had no effect. These results suggest that rOat2 accounts partly for the hepatic uptake of ketoprofen and, presumably, indomethacin as a high-affinity site and that other transporters, such as rOatps, but not rOatp2, and rOat3, are also involved. The American Society for Pharmacology and Experimental Therapeutics ER -