Preclinical @entity19 Models To Study @entity1 @entity6906 - and XXXX -Mediated Drug-Drug Interactions in Vivo.

@entity1 @entity137 @entity19 @entity6822 @entity6906 @entity3379 @entity6907 @entity1215 @entity1499 @entity9887
UNASSIGNED: The impact of @entity3379 drug uptake transporters in drug-drug interactions (DDIs) is increasingly recognized. @entity6906 and @entity6907 are @entity1 hepatic uptake transporters that can mediate liver uptake of a wide variety of drugs. Recently, we generated @entity19 with liver-specific expression of @entity1 @entity6906 or @entity6907 in a @entity19 Oatp1a/1b knockout background. Here, we investigated the applicability of these @entity19 in @entity3379 -mediated drug-drug interaction studies using the prototypic @entity3379 inhibitor @entity1215 and a good @entity3379 substrate, the anticancer drug @entity1499 ( @entity6822 ). We next assessed the possibility of @entity3379 -mediated interactions between @entity9887 and @entity6822 , a clinically relevant drug combination. Using HEK293 cells overexpressing @entity6906 or @entity6907 , we estimated IC50 values for both @entity1215 (0.9 or 0.3  M) and @entity9887 (6.7 or 7.9  M) in inhibiting @entity3379 -mediated @entity6822 uptake in vitro. Using wild-type, Oatp1a/1b-/-, and @entity6906 - or @entity6907 -humanized @entity19 , we found that @entity1215 inhibits hepatic uptake of @entity6822 mediated by the @entity19 Oatp1a/1b and @entity1 @entity6906 and @entity6907 transporters at clinically relevant concentrations. This highlights the applicability of these @entity19 models for DDI studies and may be exploited in the clinic to reduce the dose and thus @entity1499 -mediated @entity137 . On the other hand, @entity9887 inhibited only @entity1 @entity6906 -mediated hepatic uptake of @entity6822 at concentrations higher than those used in the clinic; therefore risks for @entity3379 -mediated clinical DDIs for this drug combination are likely to be low. Overall, we show here that @entity6906 - and @entity6907 -humanized @entity19 can be used as in vivo tools to assess and possibly predict clinically relevant DDIs.
