RT Journal Article
SR Electronic
T1 Kidney Cortical Transporter Expression across Species Using Quantitative Proteomics
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 802
OP 808
DO 10.1124/dmd.119.086579
VO 47
IS 8
A1 Abdul Basit
A1 Zaher Radi
A1 Vishal S. Vaidya
A1 Matthew Karasu
A1 Bhagwat Prasad
YR 2019
UL http://dmd.aspetjournals.org/content/47/8/802.abstract
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 19 transporters in the kidney cortex across five species (human, monkey, dog, rat, and mouse). In general, the abundance of all of the 19 membrane transporters was higher in preclinical species compared with human except for multidrug resistance protein 1 (MDR1), organic cation transporter (OCT) 3, and OCTN1. In nonhuman primate, the total abundance of 12 transporters for which absolute data were available was 2.1-fold higher (P = 0.025) relative to human but the percentage of distribution of these transporters was identical in both species. Multidrug resistance-associated protein (MRP) 4, OCTN2, organic anion transporter (OAT) 2, sodium/potassium-transporting ATPase, MRP3, SGLT2, OAT1, MRP1, MDR1, and OCT2 were expressed differently with cross-species variabilities 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.