FUNCTIONAL INVOLVEMENT OF RAT ORGANIC ANION TRANSPORTER 2 (SLC22A7) IN THE HEPATIC UPTAKE OF THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG KETOPROFEN

Abstract

ABSTRACT: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 > ketoprofen > 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 K m and V max values for the high-and low-affinity components for ketoprofen uptake were 0.84 and 97 M and 35 and 1800 pmol/ min/mg protein, respectively, whereas those for indomethacin were 1.1 and 140 M and 130 and 16,000 pmol/min/mg protein, respectively. The K m values of the high-affinity component were similar to those for rOat2 (3.3 and 0.37 M 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.

In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

“…All compounds showed good correlation between dog hepatocyte relay assay and in vivo intrinsic clearance values ( Fig. 1; Table 2) with the exception of ketoprofen, potentially due to the impact of extrahepatic contribution (Granero and Amidon, 2008) and uptake transporter [reported in rats (Morita et al, 2005)]. …”

“…1). The exceptions had a high hepatic uptake component by transporters [e.g., fexofenadine (Poirier et al, 2009), fluvastatin (Watanabe et al, 2010a), ketoprofen (Morita et al, 2005), prazosin (Qin et al, 1994), and bosentan (Huang et al, 2012)] or potential contribution from extrahepatic metabolism [e.g., hydrolysis of acebutolol (Andresen and Davis, (Terrier et al, 1999)]. …”

A Novel Transporter of SLC22 Family Specifically Transports Prostaglandins and Co-localizes with 15-Hydroxyprostaglandin Dehydrogenase in Renal Proximal Tubules

“…3), distinct from many OAT members that are highly inhibited by such organic anions. These characteristics suggest that OAT-PG has a unique substrate-binding site among OAT members (21,38).…”

Multidrug Resistance Protein 2-Mediated Estradiol-17β-d-glucuronide Transport Potentiation: In Vitro-in Vivo Correlation and Species Specificity

“…These concentrations model intracellular values. The hepatocyte uptakes of probenecid (Terasaki et al, 1986) and indomethacin (Morita et al, 2005) are at least partly transportermediated; thus, free intracellular concentrations may exceed the extracellular concentration of free dugs. Sulfasalazine is a compound with an extremely low passive permeability and its cellular uptake is inhibited by organic anion transport inhibitors (Liang et al, 2000).…”