RT Journal Article
SR Electronic
T1 Selective Inhibition of Human Solute Carrier Transporters by Multikinase Inhibitors
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1851
OP 1857
DO 10.1124/dmd.114.059097
VO 42
IS 11
A1 Rosie A. Johnston
A1 Tristan Rawling
A1 Ting Chan
A1 Fanfan Zhou
A1 Michael Murray
YR 2014
UL http://dmd.aspetjournals.org/content/42/11/1851.abstract
AB 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.