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Preclinical Mouse Models To Study Human OATP1B1- and OATP1B3-Mediated Drug–Drug Interactions <i>in Vivo</i>
The impact of OATP drug uptake transporters
in drug–drug
interactions (DDIs) is increasingly recognized. OATP1B1 and OATP1B3
are human hepatic uptake transporters that can mediate liver uptake
of a wide variety of drugs. Recently, we generated transgenic mice
with liver-specific expression of human OATP1B1 or OATP1B3 in a mouse
Oatp1a/1b knockout background. Here, we investigated the applicability
of these mice in OATP-mediated drug–drug interaction studies
using the prototypic OATP inhibitor rifampicin and a good OATP substrate,
the anticancer drug methotrexate (MTX). We next assessed the possibility
of OATP-mediated interactions between telmisartan and MTX, a clinically
relevant drug combination. Using HEK293 cells overexpressing OATP1B1
or OATP1B3, we estimated IC50 values for both rifampicin (0.9 or 0.3
μM) and telmisartan (6.7 or 7.9 μM) in inhibiting OATP-mediated
MTX uptake <i>in vitro</i>. Using wild-type, Oatp1a/1b–/–,
and OATP1B1- or OATP1B3-humanized transgenic mice, we found that rifampicin
inhibits hepatic uptake of MTX mediated by the mouse Oatp1a/1b and
human OATP1B1 and OATP1B3 transporters at clinically relevant concentrations.
This highlights the applicability of these mouse models for DDI studies
and may be exploited in the clinic to reduce the dose and thus methotrexate-mediated
toxicity. On the other hand, telmisartan inhibited only human OATP1B1-mediated
hepatic uptake of MTX at concentrations higher than those used in
the clinic; therefore risks for OATP-mediated clinical DDIs for this
drug combination are likely to be low. Overall, we show here that
OATP1B1- and OATP1B3-humanized mice can be used as <i>in vivo</i> tools to assess and possibly predict clinically relevant DDIs