Biomedical Engineering Reference
In-Depth Information
of acute organ rejection in transplanted patients.
123
In healthy volunteers, admin-
istration of SJW together with the HIV1 protease inhibitor indinavir produced an
approximately 57% reduction in the plasma AUC of indinavir.
124
Coadministration
of SJW with digoxin produced a 18% reduction in the plasma AUC of digoxin and a
40% increase in the expression of intestinal Pgp.
125
Other clinical studies confirmed
that coadministration of SJW significantly reduced plasma concentrations of drugs
such as oral contraceptives, cyclosporin A, tacrolimus, warfarin, omeprazole, vera-
pamil, fexofenadine, and some others, leading to important clinical implications (i.e.,
undertreatment and failure of therapies). Induction of CYP3A4 and enhanced Pgp ex-
pression have been demonstrated to be responsible for these drug-drug interactions
[for reviews, see refs. 126 to 136].
Interactions mediated by Pgp that have clinically relevant consequences have also
been reported for some excipients used in pharmaceutical formulations. In in vitro
experiments, Tween 80 was able to inhibit Pgp activity and to increase daunoru-
bicin intracellular levels in cell cultures.
137
Cremophor EL and Tween 80 (substances
used in drug formulations to dissolve some lipophylic and/or poorly soluble drugs)
were reported to increase the oral absorption of saquinavir and digoxin, respectively,
through interaction with Pgp activity.
138
,
139
In addition, food and dietary constituents
are possible Pgp modulators. A recent report described the interaction between fexofe-
nadine and grapefruit, orange, and apple juice,
140
although these complex interactions
are supported by rather contradictory results from in vivo and in vitro studies. For
example, grapefruit juice has been reported to enhance intestinal absorption and to
increase the plasma levels of the Pgp substrate talinolol in rats,
141
whereas decreased
oral bioavailability of talinolol was observed in humans after ingestion of grapefruit
juice.
142
Species differences, multiple mechanisms, and other transporters may be
the cause of this apparent discrepancy; indeed, grapefruit juice is reported to be an
enzymatic inhibitor of CYP3A, a moderate inhibitor of Pgp, and a potent inhibitor of
OATP drug-uptake transporters.
122
,
141
,
143
-
145
Possible Clinical Benefit of Drug-Drug Interactions
On the other hand, the study
of drug-drug interactions with Pgp modulators is an interesting research field, as
Pgp was discovered and described for its ability to confer the multidrug (MDR)
phenotype to cancer cells. The modulation of Pgp activity was at first seen as a
useful strategy for increasing the penetration and retention of anticancer drugs in
resistant tumor cells, thus overcoming the intrinsic or acquired resistance against
chemotherapy that occurs in several cancers. Since the mid-1980s, various clinical
trials with anticancer drugs in combination with Pgp modulators (calcium channel
blockers—nifedipine or verapamil—or cyclosporin A) have been performed.
146
-
148
Unfortunately, with only a few exceptions,
149
-
153
these studies did not show any
survival benefit for the combination of anticancer drug plus Pgp inhibitor.
154
-
158
In
addition, because the Pgp inhibitors used in those trials presented overlap in substrate
specificity with CYP3A4 inhibitors, pharmacokinetic interactions occurred, resulting
in increased toxicity. To date, some clinical trials using second- and third-generation
Pgp inhibitors with the aim to reverse MDR in tumor cells have been performed, and
others are ongoing.
159
-
161
Search WWH ::
Custom Search