IN VITRO–IN VIVO SCALE-UP OF DRUG TRANSPORT ACTIVITIES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 578

while the metabolism of cerivastatin in pooled human microsomes is inhibited by
cerivastatin with K i values of more than 30 M. Considering that the maximum

plasma unbound concentration of cerivastatin in clinical situations is around 0.1 M,

it is still possible that cyclosporin A inhibits the hepatic uptake of cerivastatin via
OATP1B1 because after oral administration of cyclosporin A, the maximum concen-
tration at the inlet to the liver is much higher than that in the circulating blood, as
discussed above. The clinical reports showing that coadministration of cyclosporin
A causes an increase in the plasma concentration of OATP substrates such as statins,
repaglinide, and bosentan also support the inhibitory effect of cyclosporin A on OATP
transporters. 2 , 77
To identify the clinically relevant drug-drug interaction for pitavastatin from in
vitro experiments, Hirano et al. have measured the inhibitory effects of several drugs
on the OATP1B1-mediated transport of pitavastatin by using OATP1B1-expressing
HEK293 cells, and they estimated the ratio of the uptake clearance in the absence
of inhibitor to that in its presence (I/R). 19 As a result, several drugs, with the ratios
greater than 2.5, have the potential to interfere with the OATP1B1-mediated uptake of
pitavastatin. Campbell et al. have examined the inhibition potencies of several drugs
on the OATP1B1-mediated uptake to screen candidate drugs producing drug-induced
hyperbilirubinemia. 78 They measured the K i values for OATP1B1-mediated E 2 17

G
uptake and compared the clinical maximum unbound concentration in the blood with
the K i values. As a result, indinavir, cyclosporin A, and rifamycin SV inhibited human
OATP1B1 at therapeutically relevant concentrations and had the potential to induce
hyperbilirubinemia, whereas saquinavir, which is also a potent inhibitor of OATP1B1,
failed to inhibit OATP1B1 in clinical situations. These results are in good agreement
with the clinical reports of drug-induced hyperbilirubinemia.
Transporter-mediated drug-drug interactions can occur during biliary excretion
as well as during hepatic uptake. Horikawa et al. have searched for drugs that can
be used as inhibitors of MRP2 in clinical situations using the same approach and
assuming that the protein unbound concentration inside the cells is equal to that in the
circulating plasma. 79 They found that some drugs (probenecid, sulfobromophthalein,
and cefodizime) had relatively smaller R values, but considering that the plasma half-
life of sulfobromophthalein and cefodizime is shorter than that of probenecid and
that probenecid is an orally administered drug, they finally proposed that probenecid
is a candidate inhibitor of MRP2 which can be used in clinical situations. They also
investigated the potential cholestatic activity of drugs in the same way and concluded
that the majority of cholestasis-inducing drugs have only a minimal inhibitory effect
on rat BSEP and MRP2. 80
Ueda et al. have established a quantitative prediction method for examining al-
terations in the pharmacokinetics of drugs caused by inhibition of uptake as well as
efflux. 81 They tried to predict the drug-drug interaction between methotrexate and
probenecid. In this strategy, the inhibitory effect of probenecid on the hepatic uptake of
methotrexate was evaluated using isolated rat hepatocytes, and the effects on its biliary
excretion were examined using bile canalicular membrane vesicles (CMVs). The de-
gree of inhibition of the uptake and efflux in vivo was comparable with that predicted
from in vitro experiments. This allowed the R values for uptake ( R uptake ) and efflux