Abstract
Multidrug and toxin extrusion protein (MATE/SLC47A) secretes metabolites and xenobiotics into the urine in the proximal tubules of the kidney. Uptake assays have been commonly used for evaluating MATE-mediated transport of new chemical entities in drug development. The purpose of this study was to examine the relationship between in vitro uptake activities by MATEs and the impact of MATE-mediated transport in in vivo renal secretion. In vitro uptake in mouse Mate1 (mMate1)-expressing human embryonic kidney 293 (HEK293) cells and several in vivo parameters from mMate1 knockout and wild-type mice were compared using nine cationic compounds (almotriptan, naratriptan, talinolol, sumatriptan, alogliptin, sitagliptin, rivaroxaban, saxagliptin, and vildagliptin). Compounds that showed statistically significant decrease in secretory clearances with respect to kidney concentrations (CLR,kidney) in mMate1 knockout mice were categorized as in vivo substrates in this study. A good correlation (R2 = 0.637) was observed between the in vitro uptake ratio and the in vivo ratio of CLR,kidney of mMate1 knockout mice and wild-type mice. This study supported the rationale of using an uptake assay to determine whether investigational compounds are the substrate of MATEs and to predict drug-drug interaction risk via renal secretion by MATE from the viewpoint of drug development in pharmaceutical companies. SIGNIFICANCE STATEMENT: We revealed that substrates judged by in vitro experiments using mouse multidrug and toxin extrusion (mMate)1-expressing cells were excreted in urine via mMate1 in vivo, and a good correlation (R2 = 0.637) was observed between in vitro uptake ratio and in vivo ratio of secretory clearance with respect to the kidney concentrations (CLR,kidney) of mMate1 knockout and wild-type mice. This study supported the rationale of using an uptake assay to predict potential human MATE1-mediated drug-drug interaction as a victim.
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