INTERPLAY OF DRUG TRANSPORTERS AND ENZYMES ON HEPATIC DRUG PROCESSING - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 716

total (CL liver , tot ) clearances existed with the physiological variables: the hepatic flow
rate ( Q ), unbound fraction (denoted by f u and f L , the unbound fractions in plasma and
tissue, respectively), CL int , met ,CL int , sec , and the basolateral influx (CL influx ) and efflux
(CL efflux ) clearances. 85 , 86 Modeling readily considers the binding of drugs that parti-
tion rapidly or slowly into RBCs. All of the above named parameters would influence
clearances in a complex fashion (Table 23.1). 85 As shown, the unbound fraction in
tissue is absent under first-order conditions, showing that tissue binding is irrelevant
for first-order conditions. It is immediately recognized from these mathematical re-
lations that the secretory intrinsic clearance (CL int , sec ) is present in the determination
of the metabolic clearance (CL liver , met ), and the metabolic intrinsic clearance term
(CL int , met ) is present in the determination of the excretory clearance (CL liver , ex ). Upon
dividing the equations, it may be shown that

CL liver , ex
CL liver , met =

CL int , sec
CL int , met

(7)

Equation (7) may be used to ascertain CL int , sec , which normally remains obscure in
the intact liver. Since CL liver , ex and CL liver , met are measured parameters, and CL int , met
may be estimated from in vitro studies, CL int , sec may be estimated from equation (7).
The next strategy was to express heterogeneity from in vitro data to the ZPBPK
model. Normally, we obtain direct measurements of the biliary clearance, CL liver , ex .
The metabolic clearance, CL liver , met , is obtained either directly or indirectly as the
difference between total and the biliary clearances. Since CL int , met may be estimated
from in vitro studies (S9, microsomal or cytosolic incubations), CL int , sec may be
approximated by equation (7), which will hold true when all of the transporters and
enzymes are evenly distributed among the zones (unpublished simulations). But equa-
tion (7) will not hold when transporter/enzyme heterogeneity and futile cycling exist,
as will be divulged later with the example on estradiol 17

-D-glucuronide (E 2 17G).
Nonetheless, the estimate of CL int , sec from equation (7) provides an initial estimate
for fitting purposes. The acinar transporter activity for the canalicular (described by
CL int , sec ) or sinusoidal (CL influx or CL efflux ) membrane may be assessed qualitatively
from confocal microscopy or from Western blotting on the relative expression of
transporter proteins in preparations derived from PP and PV hepatocytes. 47 , 87 Direct
verification of acinar transport may be secured from uptake studies involving zonally
enriched isolated hepatocytes. 46 , 47 , 87

23.5. INTERPLAY BETWEEN TRANSPORTERS AND ENZYMES

After verification of the appropriateness of the PBPK and ZPBPK models with various
drug examples, these models may then be used for examination of the interplay
between enzyme and transporter. The first account was from Sirianni and Pang, 85
who solved the equations and examined the competition between metabolism and
excretion in the PBPK model. Based on sound modeling and pharmacokinetic theory,