INTERPLAY OF DRUG TRANSPORTERS AND ENZYMES ON HEPATIC DRUG PROCESSING - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 714

and coactivators may be dependent on the culture system. Some of the models may be
cholestatic in nature, due to the inability to clear bile acids from the canaliculi when
cells are in culture. Liver slices, standardized and improved with precision cut, 78 , 79
are also useful in the investigation of drug biotransformation and toxicity. Others have
used gene-knockout or mutant animals. 80 − 83
In this chapter we highlight the use of in vitro data in unraveling the mechanisms
and rate-limiting steps underlying the hepatic clearances of drugs, some of high extrac-
tion ratios and some of poor extraction ratios. Data from the perfused liver preparation
were used since the intact organ consists of flow perfusing the hepatocytes in their
native cellular architecture and environment, and the system provides a platform to
investigate interplay of the determinants of drug clearance. 84 We demonstrate how in
vitro data on transport and metabolism may be used within simple (PBPK) and zonal
(ZPBPK) physiologically based pharmacokinetic models to provide an integrated ap-
proach to study the hepatic drug extraction. We found that there is a good correlation
between data in vitro from hepatocytes for transport and those in the perfusion sys-
tem. The resulting model may be utilized for the study and prediction of the interplay
between transporters and enzymes.

23.4. SIMPLE AND ZONAL PHYSIOLOGICALLY
BASED PHARMACOKINETIC MODELS

The zonal model is based on extending the simple physiologically based pharmacoki-
netic model (PBPK) (Figure 23.3 a ). 85 , 86 The recirculating system includes three zones
in the liver to describe heterogeneities of transporters and enzymes (Figure 23.3 b ). 14
The simple PBPK model consists of the reservoir or the central (blood) compart-
ment, the liver plasma or blood (PL), liver tissue (L), and bile compartment (bile).
Upon expansion, the new ZPBPK model comprises the periportal (PP, around the
portal region, at the inlet), midzonal, and perivenous (PV, around the central vein, at
the outlet) regions. 14 Transport clearances across the sinusoidal membrane for drug
from hepatic plasma to tissue and from tissue to hepatic plasma are characterized by
influx (CL influx ) and efflux (CL efflux ) intrinsic clearances, respectively, and these are
designated with the subscript, i to denote each i th zonal region. Drug within tissue
is metabolized by enzymes of intrinsic clearance, CL int , met ( V max / K m for first-order
condition); the V max , i for each zonal region may vary to reflect enzyme zonation,
whereas K m is constant among the zones. Biliary excretion of drug is a function of
the biliary intrinsic clearance, CL int , sec , and these may be subdivided into CL int , sec , i for
the canalicular membrane for each respective zonal region (Figure 23.3 b ). The total
intrinsic clearance of the liver is the CL int , i for i 1 to 3. Through our experience

with modeling and simulation with any given intrinsic clearance, the repetitive re-
moval of drug by enzymes or canalicular proteins that are dispersed among the zonal
regions would furnish a higher extraction efficiency than that when the enzymes or
canalicular transporters are confined within one compartment only.
Much was learned from the simpler physiologically based pharmacokinetic
(PBPK) model, since solutions for the biliary (CL liver , ex ), metabolic (CL liver , met ), and

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