Protein expression of renal uptake and efflux transporters was quantified by quantitative targeted proteomics using the surrogate
peptide approach. Renal uptake transporters assessed in this study included
organic anion transporters (OAT1-OAT4),
organic cation transporter 2 (OCT2), organic/
carnitine cation transporters (OCTN1 and OCTN2), and
sodium-glucose transporter 2 (SGLT2); efflux transporters included
P-glycoprotein,
breast cancer resistance
protein,
multidrug resistance proteins (MRP2 and MRP4), and multidrug and toxin extrusion
proteins (MATE1 and MATE2-K). Total membrane was isolated from the cortex of human kidneys (N = 41). The isolated membranes were digested by
trypsin and the digest was subjected to liquid chromatography-tandem mass spectrometry analysis. The mean expression of surrogate
peptides was as follows (given with the standard deviation, in picomoles per milligram of total
membrane protein): OAT1 (5.3 ± 1.9), OAT2 (0.9 ± 0.3), OAT3 (3.5 ± 1.6), OAT4 (0.5 ± 0.2), OCT2 (7.4 ± 2.8), OCTN1 (1.3 ± 0.6), OCTN2 (0.6 ± 0.2),
P-glycoprotein (2.1 ± 0.8), MRP2 (1.4 ± 0.6), MRP4 (0.9 ± 0.6), MATE1 (5.1 ± 2.3), and SGLT2 (3.7 ± 1.8).
Breast cancer resistance
protein (BCRP) and MATE2-K
proteins were detectable but were below the lower limit of quantification. Interestingly, the
protein expression of OAT1 and OAT3 was significantly correlated (r > 0.8). A significant correlation was also observed between expression of multiple other drug transporters, such as OATs/OCT2 or OCTN1/OCTN2, and SGLT2/OCTNs, OCT, OATs, and MRP2. These renal transporter data should be useful in deriving in vitro to in vivo scaling factors to accurately predict renal clearance and kidney epithelial cell exposure to drugs or their metabolites.