Biomedical Engineering Reference
In-Depth Information
TABLE 23.6. Assigned and Fitted Parameters to ZPBPK Based on Average Data of
Digoxin
Observed/Assigned
Fitted/Predicted
ZPBPK1
a
RBC-Alb-Perfused Livers
(20% RBC-1% Albumin)
ZPBPK2
b
Q
(mL/min/g)
0.811
Hct
0.142
V
R
(mL/g)
c
12.2
V
S
(mL/g)
d
0.149
V
L
(mL/g)
e
0.663
k
rp
(min
−
1
)
f
1.81
k
pr
(min
−
1
)
f
0.468
f
p
g
0.64
CL
influx
(mL/min/g)
h
12.1
CL
efflux
(mL/min/g)
14.3
±
388
14.1
±
204
CL
int
,
met
(mL/min/g)
0.202
±
5.49
0.197
±
2.84
CL
int
,
sec
(mL/min/g)
0.017
±
0.469
0.017
±
0.250
f
L
0.051
±
1.40
0.052
±
0.749
CL
liver
,
ex
(mL/min/g)
0.011
±
0.007
0.008
0.008
CL
liver
,
met
(mL/min/g)
0.103
±
0.051
0.093
0.094
CL
liver
,
tot
(mL/min/g)
0.123
±
0.061
0.101
0.102
E
0.144
±
0.054
0.125
0.126
Source
: ref. 89.
a
Fitted
parameters
when
the
metabolic
activity,
CL
int
,
met
,
was
distributed
heterogeneously
(10% : 30% : 60% of total intrinsic clearance in zones 1, 2, and 3, respectively).
b
Fitted parameters when CL
int
,
met
was distributed homogeneously in zones 1, 2, and 3.
c
Mean of reservoir volume normalized to averaged liver weight.
d
Sinusoidal blood volume of liver.
e
Cellular water space of liver.
f
Partition rate constants of digoxin between plasma and RBCs.
g
Unbound fraction in plasma (1 and 2% albumin) for 0.01 to 100
M of digoxin.
h
Calculated from data of Table 23.5, the in vitro, hepatocyte uptake data were scaled up with the scaling
factor (
/
, where
is 1.25
×
10
8
cells/g liver and
is 1
×
10
6
cells/mg protein).
11
zero (
f
p
=
1), steeper changes in decay are observed, and all of the clearance values
are increased further (Figure 23.11
b
). Trends simulated for the interplay between
transporters and enzymes (Figure 23.12) are identical to those of enalapril (Figures
23.6 and 23.7). The simulated results from digoxin with the ZPBPK model (with and
without heterogeneous distribution of Cyp3a2, ZPBPK1, and ZPBPK2, respectively;
Table 23.6) again confirm identical trends on the competing nature of transporters
and metabolic enzymes, as observed previously for enalapril (Table 23.4). The lack
of effect of flow on the clearances of digoxin is consistent with the fact that digoxin
is a poorly extracted compound. Due to the low
E
, the presence of heterogeneity of
enzyme CL
int
,
met
,
i
is also devoid of effect since the intrahepatic concentration gradient
is shallow, and the enzyme is unable to perturb the substrate concentration within
the cell.
Search WWH ::
Custom Search