Biomedical Engineering Reference
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Pgp-mediated efflux of calcein-AM. The crude extract and the kavalactones increased
cellular accumulation of calcein-AM significantly, causing increased intracellular flu-
orescence intensity. The concentrations needed to double baseline fluorescence were
170
M for crude extract and six kavalactones, respectively.
132
A recent in vivo study indicated that oral coadministration of kava extract
(256 mg/kg) significantly changed the pharmacokinetcs of kawain, resulting in a
tripling of kawain AUC and a doubling of
C
max
. Moreover, kava extract and kavalac-
tones significantly inhibited CYP enzymes and modestly modulated Pgp ATPase
activities in vitro. It was concluded that mechanisms by which kava extract altered
the pharmacokinetics of kawain might include inhibition of CYP450 and/or Pgp.
133
g/mL and 17 to 90
22.2.2. Interactions of Flavonoids with Drug Transporters
Flavonoids are a class of polyphenolic compounds widely present in fruits, vegeta-
bles, and plant-derived beverages, and in many herbal products marketed as over-
the-counter dietary supplements, such as St. John's wort, green tea, and milk thistle.
Concentrations of some flavonoids, such as naringin and hesperidin, abundant in fruit
juices, have been reported to be as high as 145 to 638
134
and 200 to 450 mg/L,
135
,
136
respectively. The average daily intake of total flavonoids from the U.S. diet was esti-
mated to be 200 mg to 1 g
137
−
141
. The structures of a number of flavonoid subclasses
are shown in Table 22.2. Flavonoids have long been associated with a variety of
biochemical and pharmacological properties, including antioxidant, antiviral, anti-
carcinogenic, and anti-inflammatory activities, with no or low toxicity.
142
,
143
These
health-promoting activities indicate that flavonoids may play a protective role in can-
cer prevention and cardiovascular diseases, as well as other age-related degenerative
diseases.
143
−
145
Recently, numerous studies have indicated that flavonoids could inter-
act with several efflux and uptake transporters such as Pgp, MRP1, BCRP, and OATP,
suggesting the potential roles of flavonoids for in vivo drug interactions.
30
,
34
,
120
,
146
Interactions with Pgp
The effects of flavonoids on Pgp have been studied extensively
during the past decade (Table 22.3). It was shown clearly from these studies that many
of these flavonoids demonstrated Pgp-modulating activities. However, the effects of
flavonoids, especially for some flavonols, were cell line-dependent, concentration-
dependent, and substrate-dependent. For example, in Pgp-expressing HCT-15 colon
cells, flavonols such as quercetin, kaempferol, and galangin were shown to stimu-
late adriamycin efflux.
147
In contrast, in MCF-7-ADR-resistant breast cancer cells,
quercetin was able to restore sensitivity to adriamycin and inhibit rhodamine 123
efflux.
148
Interestingly, in mouse brain capillary endothelial cells (MBEC4), quercetin
and kaempferol exhibited biphasic effects by activating Pgp at a low concentration
(10
M).
149
In rat hepatocytes,
the effects of quercetin, kaempferol, and galangin on rhodamine 123 and doxorubicin
efflux were shown to be substrate-dependent.
150
Using a purified and reconstituted
Pgp system, Shapiro and Ling reported that quercetin inhibited Pgp-mediated Hoechst
33342 efflux and enhanced its accumulation in resistant CH
R
C5 cells. This effect was,
at least partly, caused by the inhibition of Pgp ATPase activity by quercetin.
151
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M) and inhibiting Pgp at a high concentration (50
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