Abstract
Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.
Highlights
Metformin (1,1-dimethylbiguanide) is an oral insulin-sensitizing agent commonly used either alone or in combination with other antihyperglycemic drugs in patients with type 2 diabetes [1]
The 15 most potent inhibitors of OCT1, OCT2, or OCT3 were included as training compounds to test whether the pump inhibitors (PPIs) omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole are organic cation transporters (OCT) inhibitors (Figure S1)
In the present paper we focused on the uptake transporter proteins OCT1, OCT2, and OCT3 since the antidiabetic drug metformin is a substrate for each and there is already evidence that e.g. the antidiabetics repaglinide or rosiglitazone [18] as well as H2 receptor antagonists inhibit OCT function
Summary
Metformin (1,1-dimethylbiguanide) is an oral insulin-sensitizing agent commonly used either alone or in combination with other antihyperglycemic drugs in patients with type 2 diabetes [1]. Concomitant use of the potent OCT2 inhibitors cimetidine and verapamil [21] in cisplatin-treated patients resulted in a lower risk for cisplatin-related nephrotoxicity [22] since the antitumor drug cisplatin is an OCT2 substrate [23,24]. This clinical observation is supported by animal data, clearly demonstrating that cimetidinerelated inhibition of the OCT2 transporter alters cisplatin uptake in the kidney [25,26]. These examples suggest that OCT-mediated drug-drug interactions appear to be clinically relevant
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