The Influence of Oral Antidiabetic Drugs on Cellular Drug Uptake Mediated by Hepatic OATP Family Members

As patients with type 2 diabetes receiving oral antidiabetic drugs are often concomitantly treated with other drugs, they are of increased risk for drug interactions. Drugs have to be taken up into hepatocytes before their intracellular drug action or before they are metabolized, and therefore, uptake transporters are important modulators of drug pharmacokinetics and drug effects. To gain more insights into the role of uptake transporters for drug interactions, we investigated whether frequently prescribed oral antidiabetic drugs interact with the transport of drugs, mediated by the hepatic uptake transporters OATP1B1 (gene symbol SLCO1B1), OATP1B3 (gene symbol SLCO1B3) and OATP2B1 (gene symbol SLCO2B1). Using HEK293 cells recombinantly over-expressing these uptake transporters, we analysed whether glibenclamide, glimepiride, nateglinide and pioglitazone influence the transport of the model transport substrate bromosulfophthalein. Furthermore, we investigated the influence of the same oral antidiabetic drugs and of repaglinide and rosiglitazone on the uptake of the HMG-CoA-reductase inhibitor atorvastatin. The oral antidiabetic drugs glibenclamide, glimepiride and nateglinide inhibited the transport of the model substrate bromosulfophthalein, particularly the OATP2B1-mediated uptake. The OATP-mediated atorvastatin uptake was inhibited in a similar manner. For glibenclamide, inhibitory constants (Ki values) of 13.6M, 8.1M and 0.5M for OATP1B1-, OATP1B3- and OATP2B1-mediated BSP uptake were determined. In conclusion, these in vitro results demonstrate that several oral antidiabetic drugs may influence hepatic OATP-mediated drug uptake. The in vivo consequences of these results have to be analysed in further studies.