Biomedical Engineering Reference
In-Depth Information
the digoxin absorption rate constant significantly.
87
,
88
The lack of in vivo effect of
grapefruit juice on digoxin is probably due to the fact that digoxin has a high bioavail-
ability after oral administration, and therefore Pgp does not have a significant role in
determining its absorption and bioavailability after oral administration.
89
,
90
Consistent with the in vitro data of OATP inhibition, grapefruit juice decreased
the AUC,
C
max
, and urinary excretion values of fexofenadine to 30 to 40% of those
with water, with no change in the time to
C
max
, elimination half-life (
t
1
/
2
), renal
clearance, or urinary volume in humans.
25
Presumably, the mechanism underlying
this interaction is related to the reduced intestinal fexofenadine absorption due to the
inhibition of the uptake transporter OATP. A recent clinical study indicated that the
volume of grapefruit juice also had a significant effect on fexofenadine bioavailability.
A 300-mL volume of grapefruit juice decreased the AUC and
C
max
of fexofenadine
to 58 and 53%, respectively, to that following ingestion of the same volume of wa-
ter. With the total dose being the same, a 1200-mL volume of grapefruit juice had a
more pronounced effect and decreased these parameters to 36 and 33%, respectively,
of those with the corresponding volume of water. It was concluded that grapefruit
juice, at a commonly consumed volume, decreased the oral bioavailability of fexofe-
nadine, probably due to direct inhibition of uptake by intestinal OATP-A. A much
higher volume caused an additional modest effect, possibly from reduced intestinal
concentration and transit time of fexofenadine.
91
Garlic
Garlic is one of the best-selling herbal supplements in the United States and
has long been used as an herbal medicine for its lipid-lowering, cardioprotective,
antioxidant, antineoplastic, antimicrobial, and antiplatelet effects.
29
,
92
Allicin (diallyl
thiosulfinate) is believed to be one of the major active ingredients in garlic, which can
be further converted to a number of organic sulfur compounds, such as allyl, diallyl,
and methyl sulfides.
93
Recent studies indicated that garlic and its components could interact with drug
transporters via multiple mechanisms. In an in vitro study, allicin inhibited the Pgp-
mediated efflux of ritonavir significantly, increasing uptake of ritonavir in MDCK-
MDR1 cells with an IC
50
value of 119
M) remarkably
inhibited Pgp-mediated ritonavir transport across Caco-2 cell monolayers, result-
ing in an efflux ratio of ritonavir close to unity.
48
Using purified Pgp cell mem-
branes and a colorimetric ATPase assay, Foster et al.
94
showed that garlic extracts
inhibited Pgp activity significantly, although the potency was low to moderate com-
pared with verapamil, a positive control. However, in Pgp-overexpressing human
carcinoma KB-C2 cells, diallyl sulfide or diallyl trisulfide (50
M. Moreover, allicin (50
M) had no sig-
nificant effects on daunorubicin intracellular accumulation.
95
Interestingly, in Pgp-
overexpressing K562-resistant cells, exposure of a nontoxic concentration of diallyl
sulfide (8.75 mM) resulted in a time-dependent reduction of Pgp expression levels,
with a maximum effect observed at 72 hours. In addition, oral administration of diallyl
sulfide (5 mg/kg body weight) effectively reduced
Vinca
alkaloid-induced Pgp over-
expression in mouse hepatocyte.
96
In contrast, oral administration of diallyl disulfide
(200 mg/kg for 3 days) to rats induced Mrp2 expression sevenfold in renal brush
border membranes, while no Pgp induction was observed.
97
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