PT  - JOURNAL ARTICLE
AU  - Abdul Basit
AU  - Zaher Radi
AU  - Vishal S. Vaidya
AU  - Matthew Karasu
AU  - Bhagwat Prasad
TI  - Kidney cortical transporter expression across species using quantitative proteomics
AID  - 10.1124/dmd.119.086579
DP  - 2019 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.119.086579
4099  - http://dmd.aspetjournals.org/content/early/2019/05/23/dmd.119.086579.short
4100  - http://dmd.aspetjournals.org/content/early/2019/05/23/dmd.119.086579.full
AB  - Limited understanding of species differences in kidney transporters is a critical knowledge gap for prediction of drug-induced acute kidney injury, drug interaction, and pharmacokinetics in humans. Here, we report protein abundance data of nineteen transporters in the kidney cortex across five species (human, monkey, dog, rat, and mouse). In general, the abundance of all the 19 membrane transporters was higher in preclinical species as compared to human except for MDR1, OCT3 and OCTN1. In nonhuman primate, the total abundance of 12 transporters for which absolute data were available, was 2.1-fold higher (p value = 0.025) relative to human but the % distribution of these transporters was identical in both species. MRP4, OCTN2, OAT2, Na+K+ATPase, MRP3, SGLT2, OAT1, MRP1, MDR1, OCT2 were expressed differently with cross-species variability of 8.2, 7.4, 6.1, 5.9, 5.4, 5.2, 4.1, 3.3 and 2.8-fold, respectively. Sex differences were only significant in rodents and dog. High protein-protein correlation was observed in OAT1 versus MRP2/MRP4 as well as OCT2 versus MATE1 in human and monkey. The cross-species and sex-dependent protein abundance data are important for animal to human scaling of drug clearance as well as for mechanistic understanding of kidney physiology and derisking of kidney toxicity for new therapeutic candidates in drug development.SIGNIFICANCE STATEMENT Prediction of drug-induced acute kidney injury, drug interaction, and pharmacokinetics in humans from animal data requires understanding of cross-species abundance of drug transporters in drug disposition relevant tissues, e.g., kidney, liver and intestine. We quantified protein abundance data of nineteen transporters in the kidney cortex across human, monkey, dog, rat, and mouse. Significant quantitative differences were observed in transporter abundance across species. Further, few transporters were only detected in specific species, e.g., OCT3 in human and BCRP in rodents. Moreover, several proteins (OAT1 versus MRP2/MRP4 and OCT2 versus MATE1) showed significant protein-protein correlations. These quantitative protein abundance data are important for mechanistic understanding of kidney toxicity and prediction of human renal drug clearance from animal data.