Biomedical Engineering Reference
In-Depth Information
it may be deduced that suppression of one pathway should elevate the rate of drug
removal by compensatory pathways, whereas total clearance would be decreased.
85
,
87
23.5.1. Enalapril
Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, is taken up by rat
Oatp1a1 and human OATP1B2 into the liver
53
,
88
and is metabolized by the car-
boxylesterases to enalaprilat in the hepatocyte, demonstrating a moderately high ex-
traction ratio (
E
0.7) (Figure 23.4).
90
The precursor-product pair is excreted via
Mrp2/MRP2 into bile in the rat and human livers.
88
In the rat, the metabolic intrinsic
clearance (
V
max
,
met
/
K
m
,
met
under the linear conditions) was estimated from S9
fractions.
14
Further probing with zonal cells showed acinar metabolism with zonal
S9 fractions, but there was a lack of heterogeneity in the transporters, Oatp1a1 and
Mrp2 (Figure 23.5) (Table 23.2).
Taking the view that the ratio of the excretory to metabolic clearances equals the ra-
tio of the intrinsic clearances (CL
int
,
sec
/CL
int
,
met
) under linear conditions [equation (7)]
for the PBPK model, estimate of the CL
int
,
sec
may be obtained with known excretion
and metabolic clearances, and the experimentally determined value of CL
int
,
met
from
either S9 or microsomal-cytosolic preparations. The only unknown left is CL
efflux
,
which may be estimated according to the equations for the well-stirred, parallel tube,
or dispersion models [equations (4) to (6)]. The estimates may be used as initial
estimates for fitting with the simple PBPK model to the data (Table 23.3).
The parameters derived may be utilized to simulate various conditions to test the
effects of each of the variables on hepatic drug extraction. To study the interplay of
transporters and enzymes in hepatic drug processing, CL
int
,
sec
may be changed from
100% to 200%, then 50% with the PBPK model; it is noted that when CL
int
,
sec
equals
zero, the condition mimics the EHBR liver that lacks Mrp2, the transporter responsible
∼
BILE
hepatocyte
Mrp2
Mrp2
EN
A
EN
CH
2
CH
2
CH
2
CH
2
CH
2
O
CH
3
O
carboxylesterase
N
CH
NH
CH
C
CH
NH
CH
C
N
COOCH
2
CH
3
COOH
COOH
COOH
Oatp1a1
Sinusoidal
Efflux
f
p
EN
EN
bound
FIGURE 23.4.
Biological fate of enalapril (EN) and its metabolite, enalaprilat (ENA), in
rat liver. Enalapril but not its diacid metabolite enalaprilat is taken up by Oatp1a1, and both
compounds are excreted into bile via Mrp2; enalapril is metabolized to enalaprilat by the
carboxylesterases. (From ref. 87, with permission.)
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