{"doi":"10.1111/jvp.13386","title":"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.","journal":"Journal of Veterinary Pharmacology and Therapeutics","year":2023,"id":352590,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":331403,"name":"Sook Wah Yee","orcid":"0000-0001-8121-8746","position":1,"is_corresponding":false},{"id":887921,"name":"Andrew Riselli","orcid":"0000-0002-0714-5726","position":2,"is_corresponding":false},{"id":331404,"name":"Dina Buitrago Silva","orcid":"0000-0003-1656-2406","position":3,"is_corresponding":false},{"id":1098921,"name":"Craig P. Giacomini","orcid":null,"position":4,"is_corresponding":false},{"id":291250,"name":"Kathleen M. Giacomini","orcid":"0000-0001-8041-5430","position":5,"is_corresponding":false},{"id":1098922,"name":"Claire M. Brett","orcid":null,"position":6,"is_corresponding":false},{"id":900594,"name":"Mina Azimi","orcid":"0000-0001-9107-3560","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T01:12:54.209378Z","pmid":"37198956","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}