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

Abstract

The 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.