DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 388

carbon tetrachloride, which are both well-known hepatic toxicants, the expression of
the hepatic transport proteins in mice was modulated 200 , 201 : Mrp2 protein expression
was increased slightly; Mrp3 and Mrp4 expression was increased 3.6- and 16-fold,
respectively; Ntcp and Oatps were down-regulated. Collectively, hepatocytes may pre-
vent accumulation of potentially toxic chemicals and protect against subsequent liver
injury by limiting influx and enabling efficient efflux of harmful toxicants following
down-regulation of uptake transporters and up-regulation of efflux transporters.
In certain cases, impaired hepatic transport may provide protection against drug-
induced liver injury. Many electrophiles that form covalent adducts with intracellu-
lar macromolecules are detoxified by conjugation with glutathione. Mrp2-deficient
rats do not excrete glutathione into bile, resulting in about a two- to threefold in-
crease in hepatic glutathione concentrations. 202 Acetaminophen, a commonly used
antipyretic and analgesic agent, induces severe liver injury at high doses, when
acetaminophen sulfation and glucuronidation become saturated and oxidation to N -
acetyl- p -benzoquinoneimine, a potent electrophile, becomes a significant metabolic
pathway. 203 N -acetyl- p -benzoquinoneimine may be detoxified by conjugation with
glutathione, but as this cofactor becomes depleted, the electrophilic metabolite
forms covalent adducts, which can lead to necrosis. 204 Administration of toxic
acetaminophen doses (1 g/kg) induced the expected hepatotoxicity in wild-type rats
but had no apparent adverse effects in Mrp2-deficient rat livers. 205 Elevated glu-
tathione concentrations in Mrp2-deficient rats appear to play a protective role in
acetaminophen-induced hepatotoxicity; a similar effect also would be expected for
other electrophiles in Mrp2-deficient rats. 205
13.12. THE FUTURE OF HEPATIC DRUG TRANSPORT
This is an exciting era in the fast-paced field of hepatic drug transport. During the
last decade, the basolateral and apical transport proteins that play a major role in
the hepatic uptake and biliary excretion of drugs and metabolites have been identi-
fied. Although some work remains in identifying the role of proteins in the hepatic
basolateral excretion of drugs/metabolites, it is generally assumed that identifica-
tion of the key transport proteins responsible for hepatobiliary drug disposition is
nearing completion. However, the structural features of a molecule that enhance the
probability of interaction (e.g., transport, inhibition) with specific hepatic transport
proteins remains to be defined. Molecular modeling approaches hold great promise in
answering these fundamental questions. Overlapping substrate specificity for many
of these proteins suggests that the likelihood of identifying specific substrates and/or
inhibitors, which would serve as useful tools particularly in clinical studies, is remote.
Understanding which proteins are likely to be the rate-limiting step in hepatobiliary
drug disposition is essential in predicting how genetic differences, drug interactions,
and/or disease states will affect systemic, hepatic, and biliary/intestinal exposure
to drugs/metabolites. This has important implications for drug efficacy, as well as
toxicity, and much work remains to be undertaken in this area. The role of hepatic
transport proteins other than those that reside on the basolateral and apical membranes