DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 385

rosuvastatin administered alone, 164 even though metabolism is a minor route of rosu-
vastatin elimination. 165 These observations indicate that inhibition of OATP1B1 by
CsA likely plays a key role in the drug-drug interaction between rosuvastatin and
CsA. Transporter-mediated drug interactions elicited by CsA clearly are not limited
to coadministered HMG-CoA reductase inhibitors, since CsA coadministration in-
creased the plasma AUC of the endothelin receptor antagonist bosentan (30-fold)
as well as the antidiabetic repaglinide (4-fold). 166 , 167 In vivo data generated in the
rat with bosentan strongly suggest that inhibition of hepatocellular uptake plays an
important role in this severe drug interaction. The important role of OATP1B1 in the
hepatic uptake of repaglinide has been demonstrated in a separate study. 168 More-
over, this finding also suggests that inhibition of OATP1B1, in addition to CYP2C8, by
the fibric acid derivative gemfibrozil may contribute to the drug interaction between
gemfibrozil and repaglinide. Gemfibrozil also has been reported to alter the pharma-
cokinetics of the statin drugs, possibly due in part to inhibition of hepatic OATP1B1.
The use of gemfibrozil as comedication during cerivastatin therapy resulted in more
than a 5-fold increase in exposure (plasma AUC) of cerivastatin. 169 Shitara et al. 170
conducted in vitro studies to assess the relative importance of the inhibitory effects of
gemfibrozil and gemfibrozil glucuronide on CYP2C8-mediated metabolism and on
OATP1B1-mediated hepatic uptake of cerivastatin. Both gemfibrozil and gemfibrozil
glucuronide were more potent inhibitors of CYP2C8 than OATP1B1, suggesting a
major role for CYP2C8 and possibly minor involvement of OATP1B1 in this drug-
drug interaction. A less pronounced interaction was reported between gemfibrozil and
simvastatin, resulting in about a 1.9-fold increase in simvastatin acid AUC values. 171
Since no inhibition of CYP3A4 by gemfibrozil was observed in vitro, the possible
role for OATP inhibition in this drug interaction remains to be elucidated. The same
conclusion can be drawn for the drug interactions observed following coadministra-
tion of gemfibrozil with pravastatin or lovastatin. 172 , 173 Interestingly, recent in vitro
data indicate that gemfibrozil stands out among other fibric acid derivatives tested for
its potency to inhibit OATP1B1. 174
For some hepatic drug interactions, the use of animal models to elucidate the un-
derlying mechanism(s) of interaction may be justified, despite considerable species
differences in transporter affinity profiles and the fact that human OATPs are not
orthologs of rat Oatps. For instance, the pharmacokinetic interaction between the an-
tiarrhythmic drug amiodarone and digoxin has been observed in both humans 175 and
rats. 176 In vitro data suggest that inhibition of Oatp1a4-mediated hepatic uptake of
digoxin by amiodarone probably plays a predominant role in this drug interaction. 177
Less information is available regarding drug interactions mediated by hepatic uptake
transporters other than those of the SLCO family. Data generated in OAT2 expressing
oocytes strongly support a role for OAT2 in the well-known drug interaction be-
tween theophylline and erythromycin in human liver. 178 Since additional in vitro data
have demonstrated substantial inhibition of OAT2-mediated tetracycline uptake in
oocytes by acetaminophen, erythromycin, chloramphenicol, ibuprofen, bumetanide,
and furosemide, it is likely that several other drug interactions involving OAT2-
mediated transport remain to be identified. 11 Numerous drugs (including the H 2