Biomedical Engineering Reference
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that ritonavir is a potent inhibitor of the metabolizing CYP3A4 and other cytochrome
P450 isoforms
91
-
94
and that the reported ritonavir-drug interaction is likely to occur
mainly at the metabolic level,
93
-
96
this mechanism cannot explain this drug-drug
interaction, as the contribution of metabolism to digoxin elimination is negligible
in humans.
81
On the other hand, it has been demonstrated that digoxin is a good
Pgp substrate
83
,
84
that lacks Pgp inhibitor properties in vitro, and several studies re-
ported that ritonavir (like other HIV protease inhibitors) is a substrate
97
-
100
and an
inhibitor of Pgp in vitro,
97
,
99
,
101
including Pgp in renal tubules.
102
Furthermore, in
a clinical study in 12 healthy volunteers, repeated oral administration of ritonavir
increased the area under the plasma concentration-time curve (AUC) of digoxin by
86% and its volume of distribution by 77%. Ritonavir decreased the nonrenal and
renal digoxin clearance by 48 and 35%, respectively, and resulted in an increase in
digoxin terminal half-life in plasma by 156%.
103
Although the additional inhibition
of other digoxin-transporting systems by ritonavir cannot be excluded completely,
these findings support the hypothesis that therapeutic doses of ritonavir also inhibit
drug transport in humans in addition to the well-known and marked inhibitory effects
on drug metabolism.
A clinical drug-drug interaction has also been described between ritonavir and
another HIV protease inhibitor, saquinavir. When saquinavir was coadministered
with ritonavir, its oral bioavailability increased dramatically in both animals and
humans.
92
,
93
,
95
,
104
,
105
In vitro, animal and clinical experiments have shown that the
main mechanism involved in this interaction is probably ritonavir-mediated inhibition
of CYP3A-mediated drug metabolism.
95
,
96
,
101
,
106
However, a marginal role of Pgp
modulation cannot be excluded completely, because as reported above, saquinavir
and ritonavir are both substrates and inhibitors of Pgp and CYP3A, and Pgp may be
linked functionally.
51
,
70
Drug-drug interaction is also documented between the immunosuppressive
tacrolimus and verapamil. Hebert and Lam described a patient with dramatically
increased tacrolimus plasma levels and toxicity symptoms during coadministration
of verapamil.
107
Since tacrolimus and verapamil are well-known substrates and/or in-
hibitors for Pgp and CYP3A, a contribution of Pgp modulation could be postulated in
this interaction. In addition, in vitro studies showed Pgp-mediated efflux of tacrolimus
from intestinal epithelial cells (Caco-2 cells),
108
and in vivo studies demonstrated a
contribution of Pgp to oral bioavailability of tacrolimus in rats.
109
Recently, clinical
reports regarding the possible involvement of proton pump inhibitors in drug-drug
interactions have been reported. Sipe et al. described a serious case of rhabdomyoly-
sis causing atrioventricular block in a patient taking atorvastatin, esomeprazole, and
clarithromycin.
110
In patients receiving high-dose methotrexate therapy, concurrent
administration of benzimidazoles was associated with a significant decrease in clear-
ance and significantly higher plasma concentrations of methotrexate.
111
Although
proton pump inhibitors are known to interact with drug-metabolizing enzymes, since
a recent in vitro study has demonstrated that omeprazole, lansoprazole, and pantopra-
zole are substrates and inhibitors of Pgp and are able to down-regulate digoxin efflux,
44
the authors speculated that a possible contribution to this reaction could be Pgp inhi-
bition by esomeprazole altering atorvastatin's normal significant first-pass clearance.
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