Abstract
Co-administration of methotrexate (MTX) and proton pump inhibitors (PPIs) can cause a pharmacokinetic interaction that result in delayed MTX elimination and a subsequent increase in MTX blood concentrations. Human organic anion transporters (OATs) are responsible for renal tubular secretion of MTX, and are thought to be involved in this drug interaction. The aim of this study was to evaluate the inhibitory potencies of PPIs on hOAT1 and hOAT3, the two isoforms of OATs predominantly expressed in kidney proximal tubules. Using stably transfected cell systems expressing the uptake transporters HEK-hOAT1 and HEK-hOAT3, we analyzed the inhibitory potencies of omeprazole, lansoprazole and pantoprazole, on OAT-mediated [3H]ES, [3H]PAH and [3H]MTX uptake in vitro. hOAT3 is a high affinity transporter for MTX (Km = 21.17 ± 5.65 μM). Omeprazole, lansoprazole and pantoprazole inhibited [3H]MTX uptake in HEK-hOAT3 cells with IC50 of 6.8 ± 1.16 μM, 1.14 ± 0.26 μM and 4.45 ± 1.62 μM respectively and [3H]ES uptake in HEK-hOAT3 cells with IC50 of 20.59 ± 4.07 μM, 3.96 ± 0.96 μM and 7.89 ± 2.31 μM respectively. Furthermore, omeprazole, lansoprazole and pantoprazole exhibited concentration-dependent inhibition of PAH uptake on hOAT1 (IC50 = 4.32 ± 1.26 μM, 7.58 ± 1.06 μM and 63.21 ± 4.74 μM respectively). These in vitro results suggest that inhibition of [3H]MTX transport by PPIs via hOAT3 inhibition, probably explains the drug-drug interactions between MTX and PPIs and should be considered for others OATs substrates.
- anticancer agents
- drug toxicity
- drug transport
- drug-drug interactions
- membrane transport
- renal elimination
- renal transport
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics