IN VITRO–IN VIVO SCALE-UP OF DRUG TRANSPORT ACTIVITIES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 565

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0 0

0 1 10 100 1000 0 1 10 100

E-sul ( μ M) E-sul ( μ M)

(a) (b)

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0

Telmisartan E 2 17 β G

(c)

FIGURE 19.3. Specific inhibition of OATP1B1-mediated uptake by estrone 3-sulfate and
its different inhibitory effects on the uptake of pitavastatin and telmisartan in human hepato-
cytes. ( a ) Inhibitory effect of E-sul on the OATP1B1-mediated uptake of E 2 17 G (circle) and
OATP1B3-mediated uptake of CCK-8 (triangle) in transporter-expressing HEK293 cells in the
presence of 0.3% human serum albumin. ( b ) Inhibitory effect of E-sul on the uptake of pitavas-
tatin in three batches of human hepatocytes. Open circles, triangles, and squares represent the
uptake in human hepatocytes of lots OCF, 094, and ETR, respectively. ( c ) Inhibitory effect of
30 M E-sul on the uptake of telmisartan in human hepatocytes in the presence of 0.3% human
serum albumin. The y -axis represents the percentage of the saturable uptake of telmisartan and
E 2 17 G in the absence of E-sul. [( a , c ) From ref. 21; ( b ) from ref. 19. With the kind permission
of the American Society for Pharmacology and Experimental Therapeutics.]

lower than the value expected calculated from the assumption that OATP1B1 and
1B3 contribute equally to the fexofenadine uptake. Ishiguro et al. have demonstrated
that telmisartan, a novel angiotensin II receptor antagonist, could be taken up by
OATP1B3 but not by OATP1B1, and telmisartan uptake in human hepatocytes could
not be inhibited by 30

M E-sul (Figure 19.3 c ), indicating that OATP1B3 is the main
transporter involved in its uptake. 21 On the other hand, in the case of valsartan, which
is in the same category of drugs as telmisartan, both OATP1B1 and 1B3 are involved
in its uptake, indicating that the relative importance of each transporter might be dif-
ferent even between compounds with a similar chemical structure. 22 Each approach
has both advantages and disadvantages, so we recommend that users compare the
results obtained from different methods and validate their results.
Gene-silencing techniques such as antisense, ribozyme, and RNA interference
(RNAi) are also powerful tools for determining the transport activity of specific