Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

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.

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…[36][37][38][39]. Some studies suggest unexpected variables that might modify the effects of metformin, including pharmacoepidemiologic evidence that exposure to both a statin drug and metformin is necessary for an important antineoplastic effect to be observed ( 40 ) and laboratory evidence that administration of proton pump inhibitors limits cellular uptake of metformin ( 41 ).…”

A PET Tracer for Renal Organic Cation Transporters, 11C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

“…Because OCTs are all uniporters that mediate facilitated diffusion of metformin in either direction (16), the luminal extrusion of metformin into the urine is facilitated by the apical located H1/drug antiporters multidrug and toxin extrusion transporters 1 and 2 (17,18), elegantly demonstrated using proton pump inhibitors (19).…”

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

“…pharmacokinetic considerations, as conventional metformin doses used in diabetes treatment may not lead to adequate tumor concentrations of metformin, particularly for those cancers that do not express the cell surface transport proteins required for drug influx (50).…”