Adeno-associated virus-mediated knockdown demonstrates the major role of hepatic Bcrp in the overall disposition of the active metabolite of the tyrosine kinase inhibitor regorafenib in mice.

Breast cancer resistance protein (BCRP) is expressed on hepatic bile canalicular membranes; however, its impact on substrate drug disposition is limited. This study proposes an in vivo knockdown approach using adeno-associated virus encoding short hairpin RNA (shRNA) targeting the bcrp gene (AAV-shBcrp) to clarify the substrate, the overall disposition of which is largely governed by hepatic Bcrp. The disposition of the tyrosine kinase inhibitor, regorafenib, was first examined in bcrp gene knockout (Bcrp) and wild-type (WT) mice, as it was sequentially converted to active metabolites M - 2 and M - 5, which are BCRP substrates.