INTERPLAY OF DRUG TRANSPORTERS AND ENZYMES ON HEPATIC DRUG PROCESSING - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 733

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FIGURE 23.15. Fits of liver perfusion data: E 2 17G in reservoir perfusate and E 2 17G and
E 2 3S17G in bile from metastatic tumor-bearing livers ( n = 5, open symbols) and sham-
operated livers ( n = 4, solid symbols) at 4 weeks' postdevelopment of tumor to a PBPK
model . Perfusate E 2 17G (circle) and the cumulative amounts of E 2 17G (triangle up) and
E 2 3S17G (triangle down) in bile were adequately predicted by the PBPK model (solid line
for sham-operated and dashed line for metastatic tumor group). A statistical difference (*,
p < 0 . 05) was noted for the cumulative biliary excreted amounts of [ 3 H]E 2 3S17G (and the
biliary clearances) between sham-operated and metastatic tumor groups. (From ref. 105, with
permission.)

and PV regions that were assigned 13, 33, and 54% of the CL int , sult , respectively,
according to Tan et al., who reported the acinar distribution of Sult1e1 and evenness
of the sulfatases in the futile cycling of estrone sulfate. 116 With the added complexity
of futile cycling, different patterns would surface for predictions according to the
PBPK and ZPBPK models in describing changes in CL influx on the clearances of
E 2 17G. While the patterns of change predicted for E 2 17G with the PBPK model
would show similarity with those for enalapril and digoxin—an increase in CL influx
increased all clearances—patterns distinctly different from those of the PBPK model
are predicted for the ZPBPK model. According to the ZPBPK, an increase in CL influx
increases CL liver , ex and CL liver , tot but decreases the metabolic clearance, CL liver , met .
This is attributed to the perivenous zonation of Sult1e1 and even distribution of the
Mrp2 and is expected for E 2 17G, a highly cleared compound (Table 23.8). Rapid
entry into hepatocytes and absence of basolateral efflux for E 2 17G would trap larger
amounts of the substrate in zone 1, the first accessible zone after onset of perfusion,
for both sulfation and excretion. Due to less efficiency of sulfation for zone 1, more
is excreted. The perivenous abundance of Sult1e1 therefore renders a lower apparent
metabolic clearance in comparison to the scenario when Sult1e1 is evenly distributed
(Table 23.8). With changes in CL influx , the CL liver , met /CL liver , ex ratio would remain
constant for the PBPK model but is altered in the ZPBPK model, as would also
be expected for drugs undergoing futile cycling or drugs that are highly extracted
(Table 23.8).