DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 383

in transporter (and enzyme) regulation, as reported previously for MRP2, 76 should be
emphasized.
13.10. DRUG INTERACTIONS IN HEPATOBILIARY TRANSPORT
A collection of recently published clinical data has demonstrated that mechanisms
underlying hepatic drug interactions frequently extend beyond the classical involve-
ment of P450-mediated drug metabolism. 139 , 156 , 157 Transporter-related drug interac-
tions are expected to gain importance in the drug discovery and development arena,
as recent screening programs are aimed at filtering out chemical entities that display
high affinities for CYP450 enzymes. As a consequence, there is an increased likeli-
hood during drug discovery to select compounds that are transport inhibitors and/or
that depend on transporters for their elimination and/or distribution. Drug-mediated
inhibition of transporter activity, as well as induction of transport protein expres-
sion, can lead to clinically relevant drug interactions at the hepatobiliary transport
level.
A drug-drug interaction in hepatobiliary transport may occur when one drug in-
terferes with the functional activity (e.g., inhibition) and/or expression levels (e.g.,
induction) of a hepatic transport protein that is critically involved in hepatobiliary
elimination of another drug. In addition, since endogenous compounds such as bile
acids rely on hepatic transport proteins to maintain normal hepatic physiology (e.g.,
bile flow), administration of a drug that inhibits the function of key transport proteins
may cause important interactions with endogenous substances in the hepatobiliary
system. As discussed earlier in this chapter, this may lead to unexpected hepatotoxi-
city.
A substantial number of drug-drug interactions in hepatobiliary transport reported
in recent years occur at the level of hepatic uptake (see Table 13.5). Various stud-
ies have revealed interactions of drugs that inhibit the OATP family of transporters
with hepatic uptake of HMG-CoA reductase inhibitors (“statins”). For example,
concomitant treatment with the CYP3A4 inhibitor cyclosporin A (CsA) elevated
cerivastatin plasma concentrations three- to fivefold, despite its dual CYP2C8- and
CYP3A4-mediated metabolic pathway. 158 Shitara et al. 159 provided in vitro data sup-
porting the plausible mechanism for this clinically relevant drug-drug interaction by
demonstrating saturable OATP1B1-mediated uptake of cerivastatin in human hepato-
cytes. In addition, the mechanism behind this severe drug interaction was confirmed
in vivo in the rat. 160 Earlier studies had demonstrated significant interactions of CsA
with statin therapy. Examples include the 6-fold higher HMG-CoA reductase ac-
tivity in the plasma of patients receiving atorvastatin and CsA, 161 as well as the 5-
and 22-fold increase in exposure to pravastatin and lovastatin, respectively, in pa-
tients receiving these drugs in combination with CsA. 162 It should be noted, however,
that for most clinically relevant drug interactions involving statins, the relative im-
portance of CYP3A4 (or other CYPs) 163 versus OATP1B1 295 inhibition remains to
be elucidated. Coadministration of CsA results in 7- and 11-fold increases in rosu-
vastatin exposure and maximum plasma concentrations, respectively, compared to