Biomedical Engineering Reference
In-Depth Information
mice resulted in a significant increase in
Mdr1a
(
−
/
−
)
1
b
(
−
/
−
)
fetal drug concentrations
/
compared with those in
Mdr1a
(
+
/
+
)
1
b
(
+
/
+
)
fetuses. Oral coadministration of a Pgp
inhibitor (GF120918 or PSC833) to pregnant
Mdr1a
(
+
/
−
)
/
1
b
(
+
/
−
)
mice led to an
increase in fetal drug distribution similar to that reported in
Mdr1a
(
−
/
−
)
/
1
b
(
−
/
−
)
fetuses.
66
In humans, studies with in vitro perfused term placenta showed that the
fetal-to-maternal clearance index of the Pgp substrates indinavir and vinblastin was
two- to threefold higher than the maternal-to-fetal clearance.
67
Moreover, treatment
with the Pgp inhibitors PSC833 or GF120918 significantly increased the maternal-
to-fetal clearance index of the Pgp substrate saquinavir,
68
suggesting that inhibition
of Pgp activity in the placenta can affect the distribution and consequently, the fetal
toxicity and/or efficacy of Pgp substrate drugs.
/
Drug-Drug Interactions
In the literature, several drug-drug interactions mediated
by Pgp have been described (see Table 24.1). In general, study of the involvement
of Pgp in drug-drug interactions is difficult to prove in humans because due to the
overlapping substrate specificity of inhibitors and inducers between CYP3A4 and Pgp,
many drug interactions may involve both CYP3A4 enzymes and Pgp.
69
Moreover, Pgp
and CYP3A4 may be linked functionally, and several potential mechanisms by which
the functions of Pgp and CYP3A4 could be complementary have been proposed.
70
Furthermore, drug-drug interactions may involve additional ATP-binding cassette
transporters as well.
Clinical drug-drug interactions were reported in the literature between digoxin
and other drugs, such as quinidine,
71
-
73
verapamil,
74
propafenone,
75
,
76
talinolol,
77
clarithromycin,
78
itraconazole,
79
and erythromycin.
80
Coadministration of quinidine
and digoxin increased digoxin plasma concentrations, resulting in clinical toxicity.
One possible explanation proposed for this drug-drug interaction is the inhibition
of Pgp by quinidine with two main mechanisms: reduction of the renal secretion of
digoxin by blocking Pgp activity in the renal tubule, and direct inhibition (mediated
by quinidine) of the intestinal elimination of digoxin. In vitro and in vivo experi-
ments have shown that digoxin is a Pgp substrate
56
with only a minimal contribution
of metabolism to its disposition.
81
In vitro experiments demonstrated that the Pgp-
mediated transport of digoxin can be inhibited by low concentrations of quinidine,
82
and a decreased renal excretion of digoxin by quinidine and verapamil has been
demonstrated in in vitro studies using isolated perfused rat and dog kidney.
83
,
84
In
vivo experiments performed in wild-type and
Mdr1a
(
−
/
−
)
knockout mice reported
that coadministration of quinidine with digoxin in wild-type mice increased plasma
digoxin levels by more 70%, whereas there was no effect on plasma digoxin levels
for the combination in knockout mice. Furthermore, other in vivo experiments, in
rats revealed a possible interaction between quinidine and the intestinal absorption
of digoxin.
85
,
86
Finally, Drescher et al.
87
reported in humans that the direct elimina-
tion of digoxin into the intestinal lumen can be inhibited by intraluminal quinidine.
In in vitro experiments, verapamil was found to be an efficient Pgp inhibitor
40
and
has been used in vivo in several animal and human studies as a Pgp modulator.
Similar mechanisms involved in the digoxin-verapamil interaction can be postulated
for the interaction described between digoxin and propafenone, clarithromycin, or
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