TY - JOUR T1 - The JAK1/2 inhibitor ruxolitinib reverses interleukin-6-mediated suppression of drug detoxifying proteins in cultured human hepatocytes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.078048 SP - dmd.117.078048 AU - Marie Febvre-James AU - Arnaud Bruyere AU - Marc Le Vee AU - Olivier Fardel Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/11/21/dmd.117.078048.abstract N2 - The inflammatory cytokine interleukin (IL)-6, which basically activates the JAK/STAT signaling pathway, is well-known to repress expression of hepatic cytochromes P-450 (CYPs) and transporters. Therapeutic proteins, like mAbs targeting IL-6 or its receptor, have been consequently demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract IL-6 repressing effects towards hepatic detoxifying systems. Ruxolitinib was found to fully inhibit IL-6-mediated repression of CYP (CYP1A2, CYP2B6 and CYP3A4) and transporter (NTCP, OATP1B1 and OCT1) mRNA levels in primary human hepatocytes and differentiated hepatoma HepaRG cells. Such effects were dose-dependent, with ruxolitinib EC50 values around 1.0-1.2 μM and thus close to ruxolitinib plasma levels which can be reached in patients. Moreover, they were associated with concomitant restoration of CYP and drug transporter activities in IL-6-exposed HepaRG cells. By contrast, ruxolitinib failed to suppress the repression of drug detoxifying protein mRNA levels caused by IL-1β. The JAK inhibitor and anti-rhumatoid arthritis compound tofacitinib was additionally found to reverse IL-6-mediated suppression of CYP and transporter mRNA expressions. Taken together, our results demonstrated that small drugs acting as JAK inhibitors, like ruxolitinib, counteract IL-6-mediated repression of drug metabolizing enzymes and drug transporters in cultured human hepatocytes. These JAK inhibitors may consequently be hypothesized to restore hepatic detoxification capacity in vivo for patients suffering from inflammatory diseases, which may in turn cause idDDIs. ER -