INTERPLAY OF DRUG TRANSPORTERS AND ENZYMES ON HEPATIC DRUG PROCESSING - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 720

TABLE 23.2. Kinetic Parameters for Metabolism of Enalapril by S9 Enzymes Derived
from Homogeneous or Zonal Rat Hepatocytes and the Transport Constants Derived
from Initial Uptake Velocities by Homogeneous or Zonal Rat Hepatocytes
K m ( M) V max (nmol/min/g liver)

Transport a
Periportal hepatocytes 461 ± 117 1235 ± 260

Perivenous hepatocytes 441 ± 50 1352 ± 260

Homogeneous hepatocytes 344 ± 52 1430 ± 195

S9 metabolism b
Periportal hepatocytes 1049 ± 335 547 ± 310

Perivenous hepatocytes 2612 ± 236 2096 ± 600

1308 ± 419 800 ± 300 Homogeneous hepatocytes

Source : Refs. 14 and 47; with permission.
a Based on 130 × 10 6 cells per gram of liver.
b Based on 100 mg of S9 protein per gram of liver.

increased or decreased, all of the clearances increase or decrease concomitantly,
but the ratio of the biliary-metabolic clearances remains unchanged (Figure 23.6 a ),
since CL int , sec /CL int , met is constant [equation (7)]. The reverse trend holds for the
basolateral efflux clearance (Figure 23.6 b ); a decrease of CL efflux would bring about
increases in the clearances, whereas an increase in CL efflux evokes decreases in the
clearances. The ratio of drug metabolized to excreted would remain unchanged, since
CL int , sec /CL int , met is constant [equation (7)]. These changes are well predicted by the
equations shown in Table 23.1, and the results are summarized in Table 23.4.
Changes in CL int , sec or CL int , met will modulate the clearances differentially. As
may be envisioned, many scenarios may be simulated to demonstrate the competing
nature of transporters and metabolic enzymes. For enalapril that is excreted only to
a minor extent, exhibiting a low CL int , sec , the metabolic and total clearances would
be modulated only very slightly with changes in CL int , sec (Figure 23.6 d ), whereas
changes in CL int , met would evoke large changes in the total, metabolic, and biliary
clearances (Figure 23.6 c ; Table 23.4). Generally speaking, for a drug that undergoes
metabolism and biliary secretion, an increase in the intrinsic clearance of one pathway
will decrease the observed or “apparent” clearance of the alternative pathway, and
the total clearance is increased. By contrast, a decrease in intrinsic clearance of one
pathway will increase clearance of the alternative pathway and decrease the total
hepatic clearance. These compensatory mechanisms (seesaw phenomenon) are due
to changes in the intracellular substrate concentration, increasing upon inhibition and
decreasing with activation of the elimination pathways. The ratio of the biliary and
metabolic clearances will change when the intrinsic metabolic or secretory clearance
is altered (Figure 23.6 c and d ).
With the added complexity of zonation in enzymes, the ZPBPK model that en-
compasses zonal metabolism of enalapril has been added as an illustration. The total
CL int , met , being the sum of the zonal intrinsic clearances, CL int , met , i (PP, midzonal, and
PV activities represented 27, 32, and 41% of the total CL int , met from S9 studies), is the