DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 382

the dual CYP3A/Pgp substrate tacrolimus was increased due to Pgp inhibition during
isolated rat liver perfusion, 143 , 144 illustrating the controlling influence of efflux trans-
port on drug metabolism in the liver. A similar type of interplay was observed in rat
liver for the CYP3A/Pgp substrate digoxin and the Pgp inhibitor quinidine, also re-
sulting in enhanced digoxin metabolism upon coadministration. 145 In the same study,
coadministration of digoxin with the Oatp2 inhibitor rifampicin resulted in reduced
digoxin metabolism, demonstrating that hepatic uptake transporters can control ex-
posure of hepatic CYP enzymes to drugs. Inhibition of Oatp-mediated hepatic uptake
of atorvastatin by rifampicin was proposed as the predominant mechanism to explain
the reduction in atorvastatin metabolism following rifampicin coadministration in the
isolated perfused rat liver. 146 Uptake transporters regulate access of drugs to nuclear
receptor proteins (e.g., PXR, CAR), thereby influencing the intracellular concentra-
tions of drugs that act as nuclear receptor inducers. For example, human OATP1B1
expression is a major determinant of the extent of PXR activation by rifampin. 147 The
observation that chemical inhibition of hepatic Pgp results in enhanced substrate ex-
posure to CYP3A leading to increased metabolism is consistent with results obtained
with erythromycin in Mdr1a/b ( ) knockout mice; values of the average area un-

der the curve (AUC) for 14 CO 2 were increased 1.9-fold following the erythromycin
breath test in these double-knockout mice compared to control animals. 293
In addition to the functional interplay between drug-metabolizing enzymes and
transporters, the coordinated regulation of these ADME-relevant proteins also has
implications for drug disposition. The concomitant in vitro induction of Pgp and
CYP3A4 by prototypical inducers is the best known example of coordinated enzyme
and transporter regulation. 137 , 149 This concept is supported by in vivo induction data
with protease inhibitors in rats. 150 On the other hand, Matheny et al. showed that in
vivo induction of Pgp and CYP3A in rats is tissue and inducer specific. 151 The latter
observation indicates that multiple factors rather than just one orphan nuclear receptor
(such as PXR) play a role in the regulation of Pgp and CYP3A. Nevertheless, various
independent studies support the concept that regulation of CYP3A and Pgp expression
occurs via common pathways. 74 , 152 The nuclear hormone receptor PXR, believed to
predominate (hepatic) regulation of CYP3A expression, has been demonstrated to
bind at the 5 -upstream region of the MDR1 gene, thereby playing a pivotal role in
rifampin-mediated Pgp induction. 74 The multiplicity of PXR activation effects, as
well as the overlap with the effects of CAR activation, have been investigated sys-
tematically. The battery of genes reported to be under PXR regulation includes drug-
metabolizing enzymes as well as transporters such as Cyp3a11 , Ugt1a1 , Abcb1a/b ,
and Slco1a4. 153 Furthermore, it was demonstrated that 1,7-phenanthroline, which
was hypothesized initially to be a “selective” UGT inducer, concomitantly increased
Mrp3 expression in rat liver, 294 whereas Oatp1a4 expression was decreased signif-
icantly. Coordinate regulation of hepatic drug metabolizing enzymes and transport
protein expression is thought to protect the hepatocyte from intracellular accumu-
lation of toxic xenobiotics. Although the role of the orphan nuclear receptor CAR
in expression of phase 2 enzymes, including glucuronosyltransferases (UGT1A1),
has

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previously, 154 been reported its involvement in Mrp3 induction remains

controversial. 69 , 155 In this context, the plausible role of multiple nuclear receptors