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Organic cation transporter 2 (OCT2) clears the blood of cationic drugs. Efforts to understand OCT2 selectivity as a means to predict the potential of new molecular entities (NMEs) to produce unwanted drug-drug interactions typically assess the influence of the NMEs on inhibition of transport. However, the identity of the substrate used to assess transport activity can influence the quantitative profile of inhibition. Metformin and 1-methyl-4-phenylpyridinium (MPP), in particular, display markedly different inhibitory profiles, with IC50 values for inhibition of MPP transport often being more than fivefold greater than IC50values for the inhibition of metformin transport by the same compound, suggesting that interaction of metformin and MPP with OCT2 cannot be restricted to competition for a single binding site. Here, we determined the kinetic basis for the mutual inhibitory interaction of metformin and MPP with OCT2 expressed in Chinese hamster ovary cells. Although metformin did produce simple competitive inhibition of MPP transport, MPP was a mixed-type inhibitor of metformin transport, decreasing the maximum rate of mediated substrate transport and increasing the apparent Michaelis constant (K tapp) for OCT2-mediated metformin transport. Furthermore, whereas the IC50value for metformin's inhibition of MPP transport did not differ from the Ktapp value for metformin transport, the IC50 value for MPP's inhibition of metformin transport was less than its Ktapp value for transport. The simplest model to account for these observations required the influence of a distinct inhibitory site for MPP that, when occupied, decreases the translocation of substrate. These observations underscore the complexity of ligand interaction with OCT2 and argue for use of multiple substrates to obtain the needed kinetic assessment of NME interactions with OCT2. [ABSTRACT FROM AUTHOR]

AbstractDrug transporter field is rapidly evolving with significant progress in in vitro and in vivo tools and, computational models to assess transporter-mediated drug disposition and drug-drug interactions (DDIs) in humans. On behalf of all coauthors, I am pleased to share the fourth annual review highlighting articles published and deemed influential in the field of drug transporters in the year 2023. Each coauthor independently selected peer-reviewed articles published or available online in the year 2023 and summarized them as shown previously (Chothe et al. 2021; Chothe et al. 2022, 2023) with unbiased perspectives. Based on selected articles, this review was categorized into four sections: (1) transporter structure and in vitro evaluation, (2) novel in vitro/ex vivo models, (3) endogenous biomarkers, and (4) PBPK modeling for evaluating transporter DDIs (Table 1). As the scope of this review is not to comprehensively review each article, readers are encouraged to consult original paper for specific details. Finally, I appreciate all the authors for their time and continued support in writing this review. [ABSTRACT FROM AUTHOR]