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The use of herbal alternatives in modern agriculture and healthcare offers a sustainable approach to animal and human health, but raises concerns about safety, particularly regarding phytochemical interactions at membrane transport proteins. Phytochemicals – bioactive compounds found in herbs - can influence the function of the breast cancer resistance protein (BCRP/ABCG2). BCRP is a key efflux transporter in mammals and in particularly abundant in the blood-milk-barrier of lactating animals, with the potential to affect milk quality and safety. This study investigates species-specific interactions of eight selected phytochemicals with BCRP orthologs in humans, cows, sheep and goats, using a transport assay with membrane vesicles derived from species-specific BCRP-overexpressing HEK293 cells. Five phytochemicals, namely apigenin, berberine, kaempferol, N-isobutyldodeca-2E4E8Z10E/Z-tetraenamide and quercetin inhibited BCRP-mediated transport of its prototypic substrate [³H]estrone sulfate by more than 30 % in all species. IC₅₀ values and, assuming competitive inhibition, Ki values were calculated for these compounds. Apigenin and kaempferol were the most potent inhibitors with Ki values <0.1 μM in all species, while N-isobutyldodeca-2E4E8Z10E/Z-tetraenamide was the weakest inhibitor (Ki > 30 μM). No significant interspecies differences in inhibitory potency were observed. Understanding the cross-species effects of bioactive compounds on BCRP activity is essential for predicting their broader biological impacts. Similar inhibition trends across species facilitate interspecies extrapolation and minimize the amount of animal studies needed to further investigate the effect of these phytochemicals on milk composition.