Interaction of the P‐Glycoprotein‐Inhibitor Tariquidar with Hepatocellullar Organic Anion Transporting Polypeptides (OATPs)

Tariquidar is a third‐generation inhibitor of P‐glycoprotein (also MDR1 or ABCB1) and has been used in clinical trials to enhance the efficacy of anti‐cancer drugs. Ongoing positron emission tomography (PET) studies in human volunteers with [ 11 C]tariquidar revealed high radioactivity uptake in liver. We therefore aimed to test the role of hepatocellular OATPs in the uptake of tariquidar into human liver. Uptake experiments were performed using CHO cells stably transfected with OATP1B1, OATP1B3 or OATP2B1 with standard substrates in the absence and presence of tariquidar as inhibitor. Using 1 mM estrone‐3‐sulfate or 5 mM taurocholate and up to 100 mM tariquidar, no inhibition of OATP1B1 transport activity was observed suggesting that tariquidar is not interacting with OATP1B1. Using the same experimental approach, no inhibition of OATP1B3 by tariquidar was observed. In contrast, tariquidar inhibited in a concentration dependent manner OATP2B1‐mediated transport of 1 mM estrone‐3‐sulfate. Finally, we used 1 mM tariquidar as substrate for all three OATPs and found that OATP2B1 and OATP1B3 mediates uptake of tariquidar. These data demonstrate that OATPs may be involved in hepatocellular uptake of tariquidar and confirm that interaction of substrates and inhibitors with OATPs are complex processes. Interaction of tariquidar with OATPs could potentially lead to changes in pharmacokinetics of concomitantly administered (anti‐cancer) drugs.