Biomedical Engineering Reference
In-Depth Information
In addition to altering Pgp expression, St. John's wort was also shown to interact
with Pgp via modulating Pgp-mediated efflux. Using calcein-AM as a fluorescent
marker of Pgp, Weber et al.
47
reported that St. John's wort extracts, as well as some
constituents such as quercetin and hyperforin, potently modulated the transport by
Pgp in VLB cells (a human lymphocytic leukemia cell line expressing Pgp) and in
porcine brain capillary endothelial cells (PBCECs). In Caco-2 cells or canine kidney
cells stably expressing Pgp (MDCK-MDR1), hypericin and quercetin significantly
inhibited Pgp-mediated efflux of ritonavir, resulting in increased intracellular uptake
or a decreased basal-to-apical/apical-to-basal transport ratio of ritonavir.
48
Similarly,
Wang et al.
49
showed that hyperforin and hypericin significantly inhibited Pgp activity
with IC
50
values of approximately 30
M by using daunorubicin and calcein-AM as
fluorescent substrates.
Recently, several studies suggested that St. John's wort could also induce MRP2
expression both in vitro and in vivo. In human heptocellular carcinoma HepG2 cells,
a 24-hour exposure of St. John's wort or hyperforin to HepG2 cells resulted in 1.55-
to 1.72-fold increases in MRP2 mRNA levels.
50
In rats, when St. John's wort was
given at a dose of 400 mg/kg per day for 10 days, the amount of MRP2 in the liver
was increased significantly, to 304% of control. The increase in MRP2 was maximal
at 10 days after St. John's wort treatment and lasted for at least 30 days.
51
In Vivo Drug Interactions
In a single-blind, placebo-controlled parallel study, it
was shown that the area under the plasma concentration-time curve (AUC) and peak
plasma concentration (
C
max
) of digoxin (a well-known Pgp substrate
52
) were de-
creased by 25% and 26%, respectively, after the ingestion of St. John's wort for 10 days
(3
300 mg/day) by healthy volunteers.
24
Similarly, administration of St. John's wort
to eight healthy male volunteers at a dose of 300 mg three times a day for 2 weeks
decreased the bioavailability of digoxin.
31
In another study, coadministration of the
hyperforin-rich extract to healthy volunteers for 14 days significantly reduced the
AUC and
C
max
of digoxin: by 24.8% and 37%, respectively.
53
Given the fact that
digoxin undergoes limited metabolic transformation, it is likely that induction of
Pgp might be the underlying mechanism responsible for the altered pharmacokinetic
profiles of digoxin.
24
,
54
Interestingly, the effects of St. John's wort on Pgp activity appear to be exposure
duration-dependent. Using fexofenadine, a Pgp substrate with minimal metabolic
transformation,
55
,
56
Wang et al.
57
reported that a single oral dose (900 mg) of St. John's
wort to healthy volunteers increased the
C
max
of fexofenadine by 45% and decreased
the oral clearance by 20%, indicating inhibition of intestinal Pgp. However, long-term
administration (3
×
300 mg/day for 14 days) reversed the changes in fexofenadine
disposition observed with single-dose administration. The mechanism underlying this
biphasic effect of St. John's wort is possibly due to the initial inhibition of Pgp after
acute exposure, followed by a significant induction of intestinal Pgp after long-term
use.
58
In addition, coadministration of St. John's wort (3
×
300 mg/day for 14 days)
significantly decreased indinavir (a protease inhibitor) AUC by 54% and the plasma
trough concentration (
C
trough
) by 81% in healthy subjects.
59
×
Moreover, significant
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