Biomedical Engineering Reference
In-Depth Information
of inhibition (
R
)isgivenby
n
PS
int
,
n
(
+
I
)
PS
int
,
n
(
−
I
)
f
n
n
PS
int
,
n
(
n
R
=
I
)
=
R
n
I
)
=
R
n
f
n
=
−
PS
int
,
n
(
−
1
+
I
u
/
K
i
,
n
n
n
n
(28)
where PS
int
,
n
(
I
),
R
n
, and
f
n
represent the intrinsic membrane transport
clearance mediated by transporter
n
in the presence and absence of an inhibitor, the
R
value for transporter
n
, and the contribution of transporter
n
to the overall trans-
port clearance, respectively. Therefore, considering this equation, when we predict
a clinical drug-drug interaction, we must obtain information about the contribution
of each transporter to the overall membrane transport (
f
n
), the protein unbound con-
centration of the inhibitor (
I
u
), and its inhibition constant for each transporter (
K
i
,
n
).
Also,
f
n
can be obtained by several methods described in Section 19.3 and
K
i
,
n
can
be estimated from an in vitro inhibition experiment using suitable gene-expression
systems.
On the other hand, it is fairly difficult to estimate the exact
I
u
value because
I
u
is defined as the unbound concentration at the capillaries and inside the cells for
estimating drug-drug interaction involving uptake and efflux processes, respectively,
and it cannot be measured directly in vivo. Therefore, to avoid any false-negative
predictions, especially during the early phase of drug development, when an inhibitor
is administered by the intravenous route, the maximum concentration in the circulating
blood is generally used as the
I
u
value. In the case of oral administration of an inhibitor,
it is possible that the inhibitor concentration at the inlet to the liver is higher than the
maximum concentration in the circulating blood. Ito et al. have proposed an equation
for estimating the unbound maximum concentration at the inlet to the liver
75
:
+
I
), PS
int
,
n
(
−
f
u
I
max
+
k
a
DF
a
Q
h
I
u
,
in
,
max
=
(29)
where
f
u
,
I
max
,
k
a
,
D
,
F
a
, and
Q
h
represent the blood protein unbound fraction, the
maximum concentration in the circulating blood, the absorption rate constant, the
dose, and fraction absorbed into intestinal cells and the hepatic blood flow, respec-
tively. To consider the maximum concentration of an inhibitor,
k
a
and
F
a
values are
usually set at 0.1 per minute (maximum gastric emptying time
10 minutes) and
1, respectively. In interpretating the results obtained from this approach, we need to
keep in mind that even if the
R
value for the combination of drugs is calculated to
be less than 1, a drug-drug interaction does not always occur. On the other hand, if
the
R
value is nearly equal to 1, we can disregard a drug-drug interaction for that
combination of drugs.
Shitara et al. have investigated the mechanism of the drug-drug interaction between
cerivastatin and cyclosporin A by using several in vitro experimental systems.
76
They
have shown that the
K
i
values of cerivastatin for the uptake of cerivastatin both in
human hepatocytes and OATP1B1-expressing MDCKII cells are less than 1
=
M,
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