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New method prediction renal drug-drug interactions in vivo related to renal OCT2/MATE1 transporters

Global DDI Solutions

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Organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2 (MATE1/2) are major drug secretion systems. Predicting the involvement of these transporters in the metabolization pathway and the effect of new drugs on these transporters often involves in-vitro studies. The results of the in-vitro studies determine the need for in vivo studies for this specific pathway by extrapolation. Current guidelines recommend considering setting up an in-vivo drug-drug interaction (DDI) study when the maximal unbound plasma concentration / half-maximal inhibitory concentration (Imax,u/IC50) value is greater than the regulatory agency's cutoff value (e.g. ≥ 0.1 for OCT2 or MATE1 by FDA).

It remains a challenge to make a good prediction of what the effect may be in vivo based on in-vitro data. The drug has to be located in the filtrate (intracellular) to affect these transporters. Currently, a prediction is made for DDIs via OCT2/MATE1 transporters in vivo with Imax,u/IC50, which is measured in plasma. This can be one of the reasons for false- or over-prediction of OCT2/MATE-mediated DDIs. Vieira et al. explored a new in vitro tool, a double-transfected system, for DDI risk assessment related to OCT2/MATE1 transporters. Metformin is a commonly used drug excreted by OCT2/MATE1 transporters and is used as an indicator to measure the effect of other drugs (hydroxychloroquine, brigatinib, cimetidine, famotidine, pyrimethamine) on OCT2/MATE1 transporters.

First, the inhibitory effect of all drugs was studied in trans wells. They showed all MATE1 or OCT2 inhibition. Then, the effects were studied in a double-transfected system, due to the studying the inhibition effect in filtrate. Hydrochloroquine and brigatinib did not show inhibition on the MATE1 transporter in the double-transfected system, because these two drugs were not transported to the filtrate.

Famotidine, cimetidine and pyrimethamine did have an inhibitory effect on OCT2 transporters in a double-transfected system. With the use of Imax,u/IC50, all three compounds should be studied in vivo for potential DDIs. In contrast, only cimetidine and pyrimethamine should be studied for potential DDIs in vivo with this new method and famotidine not. These results correspond to the practice of monitoring interactions with cimetidine and pyrimethamine with OCT2 substrates and not for famotidine.

Optimizing in-vitro research to avoid unnecessary research and costs of in-vivo research for possible DDIs is important. It is known that OCT2/MATE1 transporters often have limited influence on DDIs, but this new method can make a better prediction of whether a new drug has an influence on these transporters and to what extent the influence is.

See for more information the article: Use of a Double-Transfected System to Predict hOCT2hMATE1-mediated Renal Drug-drug Interactions