Regorafenib Is Transported by the Organic Anion Transporter 1B1 and the Multidrug Resistance Protein 2

Abstract

Regorafenib is a small molecule inhibitor of tyrosine kinases, and has been shown to improve the outcomes of patients with advanced colorectal cancer and advanced gastrointestinal stromal tumors. The transport profiles of regorafenib by various transporters were evaluated. HEK293/organic anion transporting polypeptide 1B1 (OATP1B1) cells exhibited increased drug sensitivity to regorafenib. Regorafenib inhibited the uptake of Key words regorafenib; IC 50 ; multidrug resistance protein 2; organic anion transporting polypeptide 1B1; vectorial drug transport Regorafenib has been developed as a molecular targeted medicine for patients with metastatic colorectal cancer and advanced gastrointestinal stromal tumors, and inhibits certain tyrosine kinases. The biological effects of receptor tyrosine kinase activation are mediated by a complex cascade of intracellular signaling molecules that are potential targets for therapy, including the Raf, mitogen-activated protein extracellular kinase (MEK), and extracellular signal-regulated kinase (ERK) pathways. 1) Regorafenib is a multikinase inhibitor that targets Raf serine/threonine kinases and the vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor (PDGF) receptor-β, c-Kit, Flt3, and p38 tyrosine kinases, which blocks VEGF-and PDGF-dependent angiogenesis.2)

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

“…Recent investigations have demonstrated that regorafenib modestly inhibits the function of human OATP1B1, and that HEK293 cells overexpressing OATP1B1 exhibit increased sensitivity to regorafenib, suggesting that this multikinase inhibitor might be a transported substrate of Oatp1b‐type carriers in vivo . Our current studies, however, demonstrated that Oatp1b2 deficiency in mice does not cause differences in the pharmacokinetic profile of regorafenib after oral administration.…”

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

“…Notably, the organic-anion-transporting polypeptide (OATP) family ( SLCO genes) may be involved in the transport of TKIs used against HCC. OATP1B1 and OATP1B3 can mediate the uptake of cabozantinib [ 12 ], while OATP1B1 can also transport regorafenib [ 13 ] and probably lenvatinib [ 14 ]. However, there is a controversy regarding OATP-mediated sorafenib transport.…”

Deregulation of the Genes that Are Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Hepatocellular Carcinoma

“…The deregulation of the ADME genes involved in the metabolism and clearance of these two drugs may help to explain their relative efficacy. The key ADME genes involved in the metabolism and clearance of sorafenib and regorafenib in liver include the enzymes CYP3A4 (Ghassabian et al, 2012) and UGT1A9 (Peer et al, 2012;Miners et al, 2017), influx transporters (SLCO1B1, SLCO1B3, and SLC22A1) (Swift et al, 2013;Zimmerman et al, 2013;Ohya et al, 2015), and efflux transporters (ABCB1, ABCC2, and ABCG2) (van Erp et al, 2009;Ohya et al, 2015). While the efflux transporters were not significantly altered in HCC, the expressions of CYP3A4, UGT1A9, SLCO1B1, SLCO1B3, and SLC22A1 were all significantly downregulated in HCC, consistent with previous observations (Vander Borght et al, 2005;Tsuboyama et al, 2010;Heise et al, 2012;Ye et al, 2014).…”