Comparative Inhibitory Effects of Different Compounds on Rat Oatp1 (Slc21a1)- and Oatp2 (Slc21a5)-Mediated Transport

Purpose. The purpose of the present study is to examine the selectivity of various inhibitors towards the rat organic anion transporting polypeptides 1 (Oatp1: gene symbol Slc21a1) and 2 (Oatp2: Slc21a5). Methods. The inhibitory effects of 20 compounds on the Oatp1-mediated transport of estradiol 17-D-glucuronide and on the Oatp2-mediated transport of digoxin were examined in cDNA-transfected LLC-PK₁ cells. Results. Among the compounds examined in this study, nonsteroidal anti-inflammatory drugs, deoxycorticosterone, and quinidine preferentially inhibited Oatp1, whereas digoxin, quinine, and rifampicin preferentially inhibited Oatp2 at low concentrations. On the other hand, propionic acid, -ketoglutarate and p-aminohippurate showed no inhibitory effects on either transporter up to a concentration of 1000 M. The K_i values of ibuprofen and quinidine were estimated to be 19 and 13 times lower for Oatp1 compared with Oatp2, whereas the values for rifampicin, quinine, and digoxin were 13, 20, and 100< times lower for Oatp2 compared with Oatp1. Conclusions. At low concentrations, some of the tested inhibitors exert selective inhibition of either Oatp1- or Oatp2-mediated substrate transport. These selective inhibitors may be used at appropriate concentrations to estimate the maximum contribution of Oatp1 or Oatp2 to the total substrate uptake into rat hepatocytes.