Biomedical Engineering Reference
In-Depth Information
TABLE 23.4. Similar Trends in the Total Hepatic, Metabolic, and Excretion Clearance
When the Influx, Efflux, Metabolic, or Secretory Intrinsic Clearances Are Changed
Under Linear Conditions for Both the Single Liver Compartment PBPK Model
(Figure 23.3
a
) and the ZPBPK Model (Figure 23.3
b
)
Predictions for Clearances
Changes
CL
liver
,
tot
CL
liver
,
met
CL
liver
,
ex
↑
CL
influx
↑
↑
↑
↓
CL
influx
↓
↓
↓
↑
CL
efflux
↓
↓
↓
↓
CL
efflux
↑
↑
↑
↑
CL
int
,
met
↑
↑
↓
↓
↓
↓
↑
CL
int
,
met
↑
↑
↓
↑
CL
int
,
sec
↓
CL
int
,
sec
↓
↑
↓
↑
f
P
or
f
u
↑
↑
↑
↓
f
P
or
f
u
↓
↓
↓
basis of the simulations. With the heterogeneity of enzyme included in the ZPBPK
model, clearances and trends in the transporter-enzyme interplay are similar to
those for the simple PBPK model (cf. Figures 23.7 and 23.6). With the CL
int
,
met
unevenly dispersed among the zones, slightly higher clearances result for the ZPBPK
model than that predicted by the PBPK model. The ratio CL
liver
,
met
/CL
liver
,
ex
is not
CL
int
,
met
/CL
int
,
sec
for the ZPBPK model (Table 23.4). Similar to the results obtained
for the PBPK model (Table 23.4), decreasing the intrinsic clearance of one elimination
pathway will increase the apparent clearances of alternative removal pathways, and
the total hepatic clearance is decreased, whereas increasing the intrinsic clearance of
one pathway will decrease the apparent clearances of alternative pathways and total
clearance will be increased (Figure 23.7
c
and
d
).
There are various unexpected results in the literature: namely, the inhibition of
P-glycoprotein (Pgp or Mdr1) appeared to produce an increase in CL
liver
,
tot
.
92
,
93
The
observation is tenable only when efflux is also reduced in the presence of inhibitors.
87
It must be borne in mind that inhibitors or inducers exert multiple actions in addition
to their actions on certain pathways. Simulation studies are of great utility to show
the underlying mechanism for the changes in clearance.
23.5.2. Digoxin
The second example is digoxin (Dg3), a commonly used cardiotonic drug. In the
rat liver, digoxin is metabolized primarily by cytochrome P450 3a2 (Cyp3a2) that
is enriched in the PV zone
94
to di- and monodigitoxosides as well as digoxigenin
(Figure 23.8).
95
,
96
In addition, digoxin is excreted unchanged into bile by Pgp.
80
The
transport of digoxin into rat hepatocytes is by passive diffusion and Oatp1a4, shown in
transport studies involving Oatp1a4-transfected
Xenopus laevis
oocytes
97
−
99
or LCC-
PK1 cells.
54
Digoxin uptake into rat zonal (PP and PV) hepatocytes showed similar
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