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Transporter expression, determined by quantitative proteomics, together with PBPK models is a promising approach for in vitro-to-in vivo extrapolation (IVIVE) of transporter-mediated drug clearance. OCT2-expressing HEK293 and MDCKII cells were used to predict in vivo renal secretory clearance (CL r,sec ) of metformin. [ 14 C]-Metformin uptake clearance in OCT2-expressing cells was determined and scaled to in vivo CL r,sec by using OCT2 expression in the cells versus the human kidney cortex. Through quantitative targeted proteomics, the total expression of OCT2 in HEK293, MDCKII cells, and human kidney cortex was 369.4 ± 26.8, 19 ± 1.1, and 7.6 ± 3.8 pmol/mg cellular protein, respectively. The expression of OCT2 in the plasma membrane of HEK293 and MDCKII cells, measured using an optimized biotinylation method followed by quantitative proteomics, was 30.2% and 51.6%, respectively. After correcting for percent of OCT2 expressed in the plasma membrane and the resting membrane potential (millivolts) difference between the OCT2-expressing cells and the renal epithelial cells, the predicted CL r,sec of metformin was 250.7 ml/min, a value within the range of the observed CL r,sec of metformin. These data demonstrate the promise of using quantitative proteomics for IVIVE of transporter-mediated drug clearance and highlight the importance of quantifying plasma membrane expression of transporters and utilizing cells that mimic the in vivo mechanism(s) of transport of drugs.

The Importance of Incorporating OCT2 Plasma Membrane Expression and Membrane Potential in IVIVE of Metformin Renal Secretory Clearance