Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on OATPs and OCT1

Abstract

Objective: The uptake of drugs into hepatocytes is a key determinant for hepatic metabolism, intrahepatic action as well as their subsequent systemic plasma concentrations and extrahepatic actions. In vitro and in vivo studies indicate that many drugs used for treatment of cardiovascular diseases (e.g. oral antidiabetic drugs, statins) are taken up into hepatocytes by distinct organic anion transporters (OATPs = organic anion transporting polypeptides; gene symbol SLCO/SLC21) or organic cation transporters (OCTs = organic cation transporters; gene symbol SLC22). Since most patients with diabetes type 2 receive more than one drug and inhibition of drug transporters has been recognized as a new mechanism underlying drug-drug interactions, we tested the hypothesis whether oral antidiabetic drugs can inhibit the transport mediated by hepatic uptake transporters.

Research Design and Methods: Using stably transfected cell systems recombinantly expressing the uptake transporters OATP1B1, OATP1B3, OATP2B1, or OCT1 we analyzed, whether the antidiabetic drugs repaglinide, rosiglitazone, or metformin influence the transport of substrates and drugs [for OATPs: BSP (sulfobromophthalein) and pravastatin; for OCT1: MPP⁺ (1-Methyl-4-phenylpyridinium) and metformin].

Results: Metformin did not inhibit the uptake of OATP- and OCT1-substrates. However, OATP-mediated BSP and pravastatin uptake as well as OCT1-mediated MPP⁺ and metformin uptake was significantly inhibited by repaglinide (IC₅₀: 1.6 to 5.6 μM) and rosiglitazone (IC₅₀: 5.2 to 30.4 μM).

Conclusions: These in vitro results demonstrate that alterations of uptake transporter function by oral antidiabetics have to be considered as potential mechanisms underlying drug-drug interactions.