Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

Abstract

OBJECTIVE-The uptake of drugs into hepatocytes is a key determinant for hepatic metabolism, intrahepatic action, 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 (organic anion transporting polypeptides [OATPs]; gene symbol SLCO/SLC21) or organic cation transporters (OCTs; gene symbol SLC22). Because most patients with type 2 diabetes 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 of 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, sulfobromophthalein [BSP] and pravastatin; for OCT1, 1-methyl-4-phenylpyridinium [MPP ϩ ] and metformin).RESULTS-Metformin did not inhibit the uptake of OATP and OCT1 substrates. However, OATP-mediated BSP and pravastatin uptake and OCT1-mediated MPP ϩ and metformin uptake were significantly inhibited by repaglinide (half-maximal inhibitory concentration [IC 50 ] 1.6 -5.6 mol/l) and rosiglitazone (IC 50 5.2-30.4 mol/l).CONCLUSIONS-These in vitro results demonstrate that alterations of uptake transporter function by oral antidiabetic drugs have to be considered as potential mechanisms underlying drug-drug interactions.

Molecular and biological characterization of the Amblyomma americanum organic anion transporter polypeptide

“…Because of their ubiquitous distribution and their wide activity range as transporters of several drugs, the role of Oatp/OATP proteins in drug disposition, bio-distribution and absorption is emerging (van Montfoort et al, 2003;Faber et al, 2003;Mizuno et al, 2003;Gerloff, 2004;Niemi, 2007;Bachmakov et al, 2008). This study presents a framework for similar studies to be carried out in ticks.…”

Identification of natural products as modulators of OATP2B1 using LC-MS/MS to quantify OATP-mediated uptake

“…Roth et al (2011) reported that green tea catechins epicatechin gallate and epigallocatechin gallate significantly inhibited OATP2B1-mediated E3S uptake. Several flavonoids, silymarin flavonolignans, and antidiabetic drugs have also been reported to inhibit OATP2B1 in vitro (Bachmakov et al, 2008;Klatt et al, 2013;Kock et al, 2013;Li et al, 2014;Mandery et al, 2010). These reports demonstrated that OATP2B1 could interact with a wide range of natural products.…”

Role of Organic Anion-Transporting Polypeptides for Cellular Mesalazine (5-Aminosalicylic Acid) Uptake

“…Generation and validation of HEK-OATP1B1, HEK-OATP1B3, and HEK-OATP2B1 cells as well as the cells expressing the OATP1B1 variant *5 have been described before (Bachmakov et al, 2008). HEK293 cells stably expressing the OATP1B1 variants OATP1B1*1b and OATP1B1*15 and HEK293 cells expressing human OATP1A2 and OATP4A1 were established as described previously .…”