DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 685

OUT

Membrane

TMD TMD

IN

flavonoid

steroid-
interacting
region

steroid-
interacting
region

ATP-
binding
site

ATP-
binding
site

NBD NBD

FIGURE 22.1. Interactions of flavonoids with P-glycoprotein and related multidrug resistance
transporters. Flavonols such as kaempferide, quercetin, and galangin display bifunctional inter-
actions with NBDs at both the ATP-binding site and the hydrophobic steroid-binding region.
Prenylation of flavonoids would greatly increase the hydrophobicity of flavonoids, shifting
the flavonol binding outside the ATP-binding site to vicinal steroid-binding region and TMD
drug-binding site. (From ref. 154, with permission.)

C max , respectively. Moreover, the absolute bioavailability of paclitaxel was improved
from 2% (control group) to 6.2% (20 mg/kg quercetin treatment group). The t 1 / 2
and MRT of paclitaxel were also greatly prolonged compared to those of the control
group. Similarly, the oral administration of 40 mg/kg quercetin to pigs increased the
AUC of digoxin (p.o. dose, 0.02 mg/kg) by 170% and increased the C max by 413%.
Unexpectedly, increasing the dose of quercetin to 50 mg/kg resulted in sudden death
of two of three pigs within 30 minutes after digoxin administration. 37 The adverse
interaction observed in this study raised a serious safety concern of concomitant use
of dietary supplements and clinically important drugs, especially those with a narrow
therapeutic index. In another study, quercetin (100 M) significantly inhibited Pgp-

mediated transport of moxidectin and enhanced cellular accumulation of moxidectin
in rat hepatocytes. In addition, subcutaneous administration of quercetin (10 mg/kg)
increased the AUC of moxidectin (p.o. dose, 0.2 mg/kg) by 83.8%. 158 Interestingly, in
a study by Hsiu et al., 159 the oral administration of quercetin (50 mg/kg) to pigs and rats
resulted in decreases in the AUC of cyclosporine by 56 and 43%, respectively. How-
ever, in a recent clinical study, oral administration of quercetin (5 mg/kg, 30 minutes
or 3 days pretreatment) increased cyclosporine AUC by 36 and 47%, respectively. 38
Possible explanations for the contradictory results of cyclosporine might be species
differences, methods of administration (concomitant or separate administration), and
doses (low or high doses). All these studies indicated that flavonoid-Pgp interaction
could occur in vivo. However, the pharmacokinetic interactions observed might re-
sult from the interactions with Pgp and/or CYP3A or both, since most of these Pgp
substrates are also CYP3A substrates.