DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 386

antagonist famotidine 179 and several HIV protease inhibitors 296 ) have been identified
as potent inhibitors of OCT1 and/or OCT3, the two isoforms of the SLC22A family of
hepatic uptake transporters, but clinically relevant drug interactions involving these
transporters have not been reported.
Inhibition of canalicular transport proteins also has resulted in clinically relevant
drug interactions, including a reduction in digoxin biliary clearance (by about 40%)
in patients who also were receiving the Pgp inhibitors quinidine or verapamil. 180 , 181
More recently, inhibition of Pgp by ritonavir was proposed as the mechanism behind
the significant decrease in the nonrenal clearance of digoxin in healthy volunteers
who were coadministered the HIV protease inhibitor ritonavir. 182
Apart from the drug-drug interactions in hepatobiliary transport discussed above,
various drugs interfere with the hepatic handling of endogenous compounds, includ-
ing bilirubin, bile acids, and thyroid hormones, due to inhibition of hepatic transport
proteins. For instance, Campbell et al. demonstrated that the potency of several com-
pounds (including CsA, rifamycin SV, and the protease inhibitors saquinavir and
ritonavir) that inhibited OATP1B1-mediated transport in vitro could be correlated
directly to the incidence of hyperbilirubinemia following the use of these drugs in
humans. 9 These observations are consistent with the predominant role of OATP1B1
compared to other SLCO gene products in hepatic bilirubin uptake. 183 Several drugs
also have been reported to interact with BSEP-mediated bile acid transport, thus
causing alterations in the hepatobiliary handling of bile acids, which may lead to
hepatotoxicity. CsA, rifamycin, rifampicin, and glibenclamide were reported to cis -
inhibit BSEP activity, while trans -inhibition was observed for E 2 17G. 38 , 184 Inhibition
of BSEP also was proposed as one mechanism by which the endothelin receptor antag-
onist bosentan causes cholestasis in humans and also in rats. 27 This observation was
consistent with data generated in a systematic in vitro study examining the relationship
between the potency of compounds to inhibit bile acid transport and their cholestatic
and/or hepatotoxic potential. 185 In addition to bosentan, CsA, the endothelin-A recep-
tor antagonist CI-1034, glyburide, erythromycin estolate, and troleandomycin were
all shown to inhibit transport of taurocholate across the canalicular membrane of hu-
man hepatocytes. 185 Moreover, these compounds (except troleandomycin) also were
identified as potent inhibitors of the hepatic uptake of taurocholate. CI-1034 potently
inhibited the three major human OATP isoforms. 186
In addition to direct inhibition of transporter activity, altered transporter expres-
sion following drug-mediated transporter induction is another important mechanism
underlying drug-drug interactions in hepatobiliary transport. Indeed, as discussed
in Section 13.5, transporters are under regulatory control of orphan nuclear recep-
tors such as PXR and CAR. Therefore, repeated administration of drugs that are
ligands for these orphan nuclear receptors may lead to altered transporter expression
and activity (induction/up-regulation or down-regulation). This will cause substantial
changes in hepatobiliary elimination kinetics of drugs that are substrates for these
transporters. Clinically relevant induction of Pgp has been observed at the intestinal
level, 187 and induction of hepatic Pgp in animals has been reported. For instance, ri-
fampicin treatment resulted in a 4- to 13-fold increase in hepatic Pgp in monkeys. 188
Similarly, treatment of rats with the Pgp inducer tamoxifen resulted in about a 12-fold