Technical Abstract: Many studies investigating drug interactions with citrus compounds focus on the major grapefruit furanocoumarins bergamottin, dihydroxybergamottin and the flavonoid naringenin. This study evaluated the influence of polymethoxylated flavones (PMFs), tangeretin, nobiletin, 3,5,6,7,8,3,4'-heptamethoxyflavone, and sinensetin, as well as other minor-occuring citrus phenols hesperetin, limettin, 7-OH-coumarin, 7-geranyloxycoumarin, and eriodictyol on P-glycoprotein-mediated transport of the beta-blocker talinolol using Caco-2 cell monolayer model and to determine structure-function aspects of the interaction. The transport of talinolol across Caco-2 cells monolayers was determined in the absence and presence of distinct concentrations of the calcium-channel blocker verapamil (a known inhibitor of P-glycoprotein), and citrus compounds. A sigmoid dose-response model was used to fit the data and to estimate the IC50 values of the potential inhibitors. Results from this study show that PMFs significantly decreased talinolol transport from the basolateral to apical side, where tangeretin had the lowest IC50 of 3.2µmol/L, followed by nobiletin, heptamethoxyflavone, and sinensetin with IC50 of 3.5, 3.8 and 3.9 µmol/L, respectively. However, the efficacy of the compounds did not appear to be dependent on the number of methoxy-groups. Other citrus compounds did not have any significant effect on the transport of talinolol. This study suggests that PMFs have a high potential in the interaction with P-gp-mediated talinolol transport in Caco-2 cells. Based on their relatively low concentrations (</= 3 µg/ml) in citrus the clinical relevance of these interactions needs to be further elucidated in in vivo studies.