Biomedical Engineering Reference
In-Depth Information
Bile
Mrp2
Bcrp
Mrp2
Bcrp
HO
2
C
HO
2
C
OH
OH
OH
OH
O
O
O
Sult1e1
O
OH
OH
E
2
17G
E
2
3S17G
Sulfatase
HO
3
SO
H
Mrp3 Mrp4
Mrp3 Mrp4
Hepatocyte
Oatp1a1, Oatp1a4, Oatp1b2
f
p
E
2
17G
E
2
17G-rbc
E
2
17G
bound
FIGURE 23.13.
Schematic of the biological fate of E
2
17G in rat liver. E
2
17G is sulfated
by Sult1e1 to E
2
3S17G, which may be desulfated by arylsulfatases back to E
2
17G. Influx
transporters (Oatp1a1, Oatp1a4, and Oatp1b2) bring E
2
17G into the liver. The conjugated
estrogens, E
2
17G and E
2
3S17G, may be excreted into bile by Mrp2 and Bcrp, or efflux out by
Mrp3 and Mrp4. (From ref. 105, with permission.)
membrane, the metabolite appears exclusively in bile.
105
Both E
2
17G and E
2
3S17G
are excreted by Mrp2, and to a lesser extent Bcrp, into bile.
106
−
109
The efflux of E
2
17G
at the basolateral membrane may be mediated by Mrp3 and Mrp4,
110
,
113
whose levels
are very low at physiological conditions unless cholestasis occurs.
9
,
111
,
112
,
114
In a metastatic liver tumor model in which microcirculatory changes were absent
in male Wag/Rij rats,
115
enzymes and transporters in the peritumor tissue were found
to be altered with tumor progression. Specifically, Oatp1a1 and Oatp1b2 were de-
creased significantly (40%) compared to those in sham-operated rat liver; sulfatase
activity was unchanged, whereas sulfotransferase activity by Sult1e1 was increased
significantly (Figure 23.14).
105
These in turn altered the removal kinetics E
2
17G (Fig-
ure 23.15). The data from both sham-operated and metastatic tumor liver have been
fit to a PBPK model that includes futile cycling. The fit revealed a decreased influx
clearance (CL
influx
, 40% decrease) and increased sulfation activity (CL
int
,
met
, 40%)
(Table 23.7). The model is able to predict the perfusion data (Figure 23.15), with and
without tumor, and altered protein levels of enzyme and uptake transporters (Figure
23.14). For E
2
17G that is taken up rapidly, however, the decrease in CL
influx
in tumor
liver would not reduce the overall clearance of E
2
17G, since the CL
influx
remains to
be very high. When the decrease in CL
influx
exceeds 40% (Figure 23.16), the reduc-
tion in clearance (total, biliary, and metabolic) would then become apparent. For this
flow-limited and highly cleared substrate, increased Sult1e1 levels increases sulfation
and the net metabolic clearance, bringing about a reduction in the biliary excretion
clearance (Table 23.7).
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