Interactions of the Janus kinase (JAK) inhibitor ruxolitinib with solute carriers (SLCs) remain incompletely characterized. The present study was therefore designed to investigate this issue. The interactions of ruxolitinib with SLCs were analyzed using transporter-overexpressing HEK293 cells. Substrate accumulation was detected by spectrofluorimetry, LC-MS/MS spectrometry or scintillation counting. Ruxolitinib was found to potently inhibit the activities of OAT3, OCT2, MATE1 and MATE2-K (IC50 < 10 µM). It blocked OAT1, OAT4, OATP1B1, OATP1B3, OATP2B1 and OCT3, but in a weaker manner (IC50 > 10 µM), whereas OCT1 was not impacted. No time-dependent inhibition was highlighted. When applying the US FDA criteria for transporters-related drug-drug interaction risk, OCT2 and MATE2-K, unlike MATE1 andOAT3, were predicted to be in vivo inhibited by ruxolitinib. Cellular uptake studies additionally indicated that ruxolitinib is a substrate for MATE1 and MATE2-K, but not for OAT3 and OCT2. Ruxolitinib in vitro blocked activities of most of SLC transporters. Only OCT2 and MATE-2K may be however clinically inhibited by the JAK inhibitor, with the caution for OCT2 that in vitro inhibition data were generated with a FDA-non recommended fluorescent substrate. Ruxolitinib MATEs-mediated transport may additionally deserve attention for its possible pharmacological consequences in MATE-positive cells.
Differential in vitro interactions of the Janus kinase inhibitor ruxolitinib with human SLC drug transporters.