Characterization of P‐glycoprotein orthologs from human, sheep, pig, dog, and cat

Abstract

AbstractThe ATP‐binding cassette transporter P‐glycoprotein (P‐gp) limits the oral bioavailability of many drugs. Although P‐gp has been well studied in humans and mice, little is known about the substrate specificities of many of its species orthologs. To address this, we performed in vitro analysis of P‐gp transporter function using HEK293 cells stably expressing human, ovine, porcine, canine, and feline P‐gp. We also employed a human physiologically based pharmacokinetic (PBPK) model to assess variations in digoxin exposure resulting from altered P‐gp function. Compared to human P‐gp, sheep P‐gp had significantly less digoxin efflux (2.3‐fold ±0.04 vs. 1.8‐fold ±0.03, p < .0001) and all species orthologs had significantly less quinidine efflux compared with human P‐gp (p < .05). Human P‐gp also had significantly greater efflux of talinolol compared to sheep and dog P‐gp (1.9‐fold ±0.04 vs. 1.6‐fold ±0.06, p = .003 and 1.6‐fold ±0.05, p = .0002, respectively). P‐gp expression protected all lines against paclitaxel‐induced toxicity, with sheep P‐gp being significantly less protective. The inhibitor verapamil demonstrated dose‐dependent inhibition of all P‐gp orthologs. Finally, a PBPK model showed digoxin exposure was sensitive to altered P‐gp activity. Overall, our study found that species differences in this major drug transporter exist and that the appropriate species ortholog of P‐gp should be evaluated during veterinary drug development.