Biomedical Engineering Reference
In-Depth Information
In addition to modulating Pgp activity, grapefruit juice has been shown to interact
with Pgp via other mechanisms. Using an ATP-hydrolysis assay, Wang et al.
70
reported
that bergamottin increased ATP hydrolysis approximately 2.3-fold, with a
K
m
value of
8
M, suggesting that grapefruit juice components might also modulate Pgp ATPase
activity. In an in vitro study, exposure of grapefruit juice as well as kaempferol and
naringenin to human proximal tubular HK-2 cells for 4 days decreased Pgp mRNA
and protein levels significantly in a dose-dependent manner.
80
Recently, it was shown that grapefruit juice could also interact with other drug
transporters. In human MRP2 transfected porcine kidney epithelial cells (LLC-
MRP2), ethyl acetate extracts of grapefruit juice or its components (bergamottin
and 6
,7
-dihydroxybergamottin) inhibited MRP2-mediated transport of vinblastine
and saquinavir significantly.
75
Interestingly, recent interaction studies on grape-
fruit juice and fexofenadine (a substrate for both Pgp and human OATP or rat
oatp
55
) indicated that grapefruit juice preferentially inhibited human OATP and rat
oatp rather than Pgp in cell culture studies at a concentration of 5% of normal
strength. Several constituents, including bergamottin, 6
,7
-dihydroxybergamottin,
naringenin, and hesperidin, at a concentration of 50
M significantly inhibited fex-
ofenadine uptake mediated by rat Oatp3. Moreover, 6
,7
-dihydroxybergamottin po-
tently inhibited rat oatp1 with an IC
50
value of 0.28
M, whereas no significant
inhibitory effect on Pgp was observed.
25
Moreover, in human embryonic kidney
293 cells stably expressing OATP-B, grapefruit juice at a concentration of 5% sig-
nificantly inhibited OATP-B-mediated uptake of estrone 3-sulfate by 82%. Major
grapefruit juice constituents, including naringin, naringenin, quercetin, bergamottin,
and 6
,7
-dihydroxybergamottin, at a concentration of 10
M, also significantly in-
hibited OATP-B-mediated uptake of estrone 3-sulfate by 39, 28, 21, 60, and 43%,
respectively.
81
In Vivo Drug Interactions
Several studies have indicated that grapefruit juice can
produce significant increases in the AUC (45 to 60%) and
C
max
(35 to 43%) of
cyclosporine in healthy subjects.
82
−
84
Compared with CYP3A4, intestinal Pgp was
suggested to be a more important determinant of cyclosporine bioavailability, pre-
sumably by being a rate-limiting step in drug absorption.
85
In rats, grapefruit juice caused a nearly twofold increase in
C
max
and more than
a 35% increase in AUC of talinolol, indicating an important role of Pgp in talinolol
disposition.
72
In a recent clinical study, however, intake of grapefruit juice signifi-
cantly decreased the AUC,
C
max
, and urinary excretion of talinolol to 56, 57, and 56%,
respectively.
86
One possible explanation for this discrepancy is the difference in ex-
perimental protocols (adjusted and unadjusted pH for grapefruit juice) since talinolol
has a pH-dependent intermediate lipid solubility and low water solubility. Another
explanation suggested by the authors is that other intestinal uptake transporters might
be responsible for talinolol uptake, and grapefruit juice may have species-different
effects on these transporters.
86
On the other hand, inhibition of Pgp by grapefruit juice had no significant effects
on digoxin pharmacokinetics. In two clinical studies, grapefruit juice did not affect
AUC,
C
max
, elimination half-life, or renal clearance of digoxin, although it decreased
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