DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 684

of rhodamine 123 to another site on Pgp and stimulated rhodamine 123 transport. 153
Alternatively, the difference in experimental conditions, such as the different cell
lines, the different substrates and their concentrations, and the concentrations of
flavonoids used, might contribute to the discrepancies as well. As shown in the
MBEC4 study, low concentrations of quercetin and kaempferol activated Pgp pos-
sibly via enhancing the phosphorylation (and hence activity) of Pgp, whereas high
concentrations of quercetin and kaempferol inhibited Pgp directly. 149 Despite these
earlier controversial observations, the majority of recent studies have shown that
many flavonoids aglycones have an inhibitory activity on Pgp-mediated drug transport
(Table 22.3).
Using purified C-terminal nucleotide-binding domain (NBD2) from mouse Pgp,
Conseil et al. studied the structure-activity relationship of flavonoids interacting with
Pgp based on their binding affinity. As a suitable tool for the rapid screening of
Pgp modulators, NBD2 contains an ATP-binding site as well as a close but distinct
hydrophobic steroid RU486-binding site. 30 It was shown in this study that flavones
(apigenin) and flavonols (quercetin) had higher binding affinity than flavanones (narin-
genin), isoflavones (genistein), or glycosylated derivatives (rutin). Interestingly, the
flavonol kaempferide exibited bifunctional interactions with both the ATP-binding
and hydrophobic steroid-binding sites. 30 It was shown in other studies that among
a total of 29 flavonoids tested, flavonols were able to bind to the ATP-binding site
but flavones did not, suggesting the essential roles of hydroxyl at position 3 on the
C ring in interacting with ATP-binding site. 154 Moreover, hydrophobic substitution
by prenylation at either position 6 or 8 on the A ring increased the binding affinity
of flavonoids for Pgp NBD2 significantly and abolished the interactions of flavonols
with the ATP-binding site. 154 Based on these findings, a tentative mechanism for the
interaction of flavonoids with Pgp was proposed by Di Pietro et al. 154 In this model,
flavonols appear to interact with the ATP-binding site via hydroxyl groups at positions
3 and 5 on the A or C ring, whereas the rest of the molecule would interact with the
hydrophobic steroid-binding region. Increasing hydrophobicity by prenylation will
shift flavonol binding from the ATP-binding site to the vicinal steroid-binding and
transmembrane domain (TMD) (Figure 22.1).
Additional structure-activity relationship studies using NBD2 and cell lines sug-
gest that high Pgp-modulating activities are associated with molecules containing a
2-3 double bond (planar structure), 3- and 5-hydroxyl groups, and hydrophobic groups
on the A or B ring. Moreover, glycosylation would dramatically decrease flavonoid
Pgp-modulating activity, as exemplified by rutin, heperidin, and naringin (Table 22.3).
With regard to flavanols (e.g., catechin, catechin gallate, EGC, EGCG), the presence
of a galloyl moiety on the C ring increases their activities markedly. 152 , 154 − 156
The pharmacokinetic interactions of flavonoids with drug transporters have been
reported in a number of studies, most of which were focused on the interactions
between Pgp and quercetin. Using paclitaxel as a Pgp substrate, Choi et al. 157 inves-
tigated the effects of quercetin on paclitaxel pharmacokinetics in rats. It was shown
in this study that the oral administration of quercetin increased the AUC and C max of
paclitaxel (po dose, 40 mg/kg) in a dose-dependent manner. At a dose of 20 mg/kg,
quercetin administration resulted in a 3.1- and 2.7-fold increase in paclitaxel AUC and