Modulation of efflux transporters by flavonoids: Drug interactions and MDR reversal

Flavonoids are polyphenolic compounds rich in our diet and in many herbal preparations. P-glycoprotein and breast cancer resistance protein (BCRP) are the efflux transporters with important role in cancer multidrug resistance (MDR) and in drug disposition. In order to predict potential flavonoid-drug interactions, the interactions of these compounds with P-glycoprotein and BCRP were investigated in this thesis dissertation.; The flavonoids biochanin A, morin, phloretin and silymarin were shown to inhibit P-glycoprotein-mediated transport and the underlying mechanisms may involve direct binding of these compounds to P-glycoprotein, and may be not identical for different flavonoids. Biochanin A and silymarin, the major components of the herbal preparations red clover (Trifolium pratense ) extracts and milk thistle (Silybum marianus), were further evaluated in the human intestinal Caco-2 cell model for their potential for drug interactions. Both compounds significantly increased the apparent permeability of digoxin across Caco-2 cell monolayers in the apical to basolateral direction and decreased the apparent permeability of digoxin in the basolateral to apical direction, indicating a potential for intestinal drug interactions.; The flavonoid aglycones were also shown for the first time to be potent BCRP inhibitors. The EC50 values of eight frequently ingested flavonoids apigenin, biochanin A, chrysin, genistein, kaempferol, hesperetin, naringenin and silymarin were estimated to be within low micromolar range. These flavonoids were shown to inhibit BCRP additively. By comparing the EC50 values of 26 flavonoids, the structural features of flavonoids that are important for BCRP inhibition were identified. A QSAR model was also developed and validated, and may be used to predict the inhibition activity of other untested flavonoids. The potential of flavonoids for in vivo pharmacokinetic interactions through BCRP inhibition was tested in Sprague Dawley rats and mdr1a/1b (-/-) mice using topotecan as a model BCRP substrate. The flavonoids chrysin and 7,8-benzoflavone, potent inhibitors of human BCRP, had no significant effect on topotecan pharmacokinetics following oral administration. In evaluating possible reasons for this in vitro-in vivo inconsistency, we found that chrysin and 7,8-benzoflavone only potently inhibit human BCRP, but not mouse BCRP. However, other possibilities responsible for this discrepancy can not be excluded at this time.