Quantitative Proteomic Map of Enzymes and Transporters in the Human Kidney: Stepping Closer to Mechanistic Kidney Models to Define Local Kinetics

Abstract

The applications of translational modeling of local drug concentrations in various organs had a sharp increase over the last decade. These are part of the model-informed drug development initiative, adopted by the pharmaceutical industry and promoted by drug regulatory agencies. With respect to the kidney, the models serve as a bridge for understanding animal vs. human observations related to renal drug disposition and any consequential adverse effects. However, quantitative data on key drug-metabolizing enzymes and transporters relevant for predicting renal drug disposition are limited. Using targeted and global quantitative proteomics, we determined the abundance of multiple enzymes and transporters in 20 human kidney cortex samples. Nine enzymes and 22 transporters were quantified (8 for the first time in the kidneys). In addition, > 4,000 proteins were identified and used to form an open database. CYP2B6, CYP3A5, and CYP4F2 showed comparable, but generally low expression, whereas UGT1A9 and UGT2B7 levels were the highest. Significant correlation between abundance and activity (measured by mycophenolic acid clearance) was observed for UGT1A9 (Rs = 0.65, P = 0.004) and UGT2B7 (Rs = 0.70, P = 0.023). Expression of P-gp ≈ MATE-1 and OATP4C1 transporters were high. Strong intercorrelations were observed between several transporters (P-gp/MRP4, MRP2/OAT3, and OAT3/OAT4); no correlation in expression was apparent for functionally related transporters (OCT2/MATEs). This study extends our knowledge of pharmacologically relevant proteins in the kidney cortex, with implications on more prudent use of mechanistic kidney models under the general framework of quantitative systems pharmacology and toxicology.