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Several US Food and Drug Administration (FDA) approved drugs have been identified as MATE1 and MATE2‐K substrates. Of those, only metformin is considered a well‐established in vivo MATE substrate for use in clinical interaction studies [89]. By comparison, several inhibitors of MATE1 and MATE2‐K have been recommended for clinical interaction studies, including cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, and vandetanib [89]. An increase in the exposure (area under the plasma concentration‐time curve) in the presence versus absence of a transport inhibitor defines the interaction as strong if ≥5‐fold increase is observed and moderate if a 2‐ to 5‐fold increase is noted [90]. While the FDA does not consider metformin (substrate) or any of the inhibitors as index drugs for prospective drug–drug interaction studies (due to the promiscuity for multiple transporters), clinical interaction studies are advocated to inform about potential interactions during concomitant usage of two drugs. The FDA specifies that if renal secretion accounts for ≥25% of systemic clearance for an investigational drug that has been identified as a MATE substrate from in vitro studies or if there are concerns about kidney toxicity, then a clinical transporter drug–drug interaction study is warranted [90]. Additionally, if an investigational drug is identified as a MATE inhibitor from in vitro studies, then a clinical drug interaction study would incorporate a known substrate that represents the MATE pathway. However, the criteria of the substrate being a likely concomitant drug may not be met in many circumstances.

The drug development process, through preclinical studies, identifies compounds where renal clearance accounts for a significant percentage of the total body clearance. However, since renal clearance can occur through both filtration and secretion, it is important to distinguish the percentage that is accounted for by secretion, in this case by MATE1 or MATE2‐K. The FDA recommends a 25% threshold systemic clearance due to secretion clearance for further evaluation. Additionally, if there is potential nephrotoxicity of a transporter substrate, then drug–drug interactions should be considered since reduced MATE activity could potentiate cellular toxicity. Table 3.3 has collated clearance and exposure data for compounds that are MATE1 and MATE2‐K substrates in humans. Inhibitors of MATE transporters can reduce renal secretory clearance pathway through the relationship of CL_secretion = CL_total − CL_Filtration. The filtration clearance can be estimated by the glomerular filtration rate multiplied by the unbound fraction of the substrate. Highly relevant in Table 3.3 is the expected area under the plasma concentration data for the substrates, as reductions in renal clearance will lead to increased exposures for the substrates and potential toxicities.