title: Selective inhibition of human solute carrier transporters by multikinase inhibitors.
abstract: Solute carrier (SLC) transporters regulate the cellular influx and disposition of endogenous and xenobiotic compounds, including anticancer agents such as the multikinase inhibitors (MKIs). Recent evidence suggests that MKIs may also inhibit SLC-dependent transport of coadministered drugs, although present information on the relative susceptibilities of multiple SLC transporters is limited. This study evaluated 18 MKI drugs and metabolites as inhibitors of prototypic substrate uptake by 13 SLC transporters that were overexpressed in human embryonic kidney cells. Organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 2B1, organic anion transporter 3 (OAT3), and organic cation transporter 1 (OCT1) were inhibited by most MKIs, whereas substrate uptake by OATP1B1, OAT1, 2, and 4, OCT2 and 3, and organic zwitterion/cation transporter 1 (OCTN1) was less susceptible to inhibition; OCTN2 was also inhibited by cediranib. In further studies, IC50 values were determined for the most effective MKIs, and erlotinib and cediranib were found to be potent competitive inhibitors of OATP2B1 (Ki = 41 nM) and OATP1A2 (Ki = 33 nM), respectively. From predictive approaches, several MKI-SLC interactions were found to be of potential in vivo significance.
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School (R.A.J., M.M.) and Faculty of Pharmacy (T.C., F.Z.), University of Sydney, New South Wales, Australia; and Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, New South Wales, Australia (T.R.).
authors.forename: Rosie A
authors.initials: RA
authors.lastname: Johnston
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School (R.A.J., M.M.) and Faculty of Pharmacy (T.C., F.Z.), University of Sydney, New South Wales, Australia; and Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, New South Wales, Australia (T.R.).
authors.forename: Tristan
authors.initials: T
authors.lastname: Rawling
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School (R.A.J., M.M.) and Faculty of Pharmacy (T.C., F.Z.), University of Sydney, New South Wales, Australia; and Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, New South Wales, Australia (T.R.).
authors.forename: Ting
authors.initials: T
authors.lastname: Chan
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School (R.A.J., M.M.) and Faculty of Pharmacy (T.C., F.Z.), University of Sydney, New South Wales, Australia; and Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, New South Wales, Australia (T.R.).
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School (R.A.J., M.M.) and Faculty of Pharmacy (T.C., F.Z.), University of Sydney, New South Wales, Australia; and Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, New South Wales, Australia (T.R.) michael.murray@sydney.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Murray
mesh_terms: D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D047428:Protein Kinase Inhibitors