%0 Journal Article %T Effect of Gevokizumab on Interleukin-1 beta-Mediated Cytochrome P450 3A4 and Drug Transporter Repression in Cultured Human Hepatocytes %+ Technologie Servier %+ Institut de recherche en santé, environnement et travail (Irset) %A Moreau, Amelie %A Le Vee, Marc %A Jouan, Elodie %A Denizot, Claire %A Parmentier, Yannick %A Fardel, Olivier %< avec comité de lecture %@ 0378-7966 %J European journal of drug metabolism and pharmacokinetics %I Springer %V 42 %N 5 %P 871-878 %8 2017-10 %D 2017 %R 10.1007/s13318-017-0406-1 %M 28260174 %K Denosumab %K Drug Transporter %K Human Hepatocyte %K Probenecid %K Tocilizumab %Z Life Sciences [q-bio]/Ecology, environment/HealthJournal articles %X Background and objectives - Gevokizumab is a potent anti-interleukin (IL)-1β neutralizing monoclonal antibody (mAb), which may be used for treating inflammatory or autoimmune diseases. The present study was designed to characterize the potential effects of this mAb towards well-established IL-1β-mediated repression of hepatic drug detoxifying proteins, like cytochrome P450 (CYP) 3A4 and drug transporters. Methods - Primary cultured human hepatocytes were exposed to various concentrations of IL-1β in the absence or presence of gevokizumab (5 µg/mL); mRNA expression and activity of CYP3A4 and transporters were next determined. Results - Gevokizumab was found to down-modulate, but not abolish, the repression of CYP3A4 and drug transporter mRNAs caused by IL-1β in human hepatocytes, through shifting up IL-1β half maximal inhibitory concentration (IC) values by factors ranging from 6.8 to 10.4. The mAb concomitantly shifted IL-1β IC values towards CYP3A4 activity from 22.0 pg/mL (in the absence of gevokizumab) to 796 pg/mL (in the presence of gevokizumab) and counteracted the decrease of organic anion-transporting polypeptide activity occurring in response to 50 pg/mL IL-1β, but not that occurring at higher IL-1β concentration (1000 pg/mL). Conclusion - Gevokizumab attenuates, but not abolishes, IL-1β-mediated functional repression of CYP3A4 and drug transporters in human hepatocytes, which agrees with the fact that the mAb is considered as a modulator and not a blocker of IL-1β signaling. This attenuation of IL-1β-mediated down-regulation of hepatic detoxifying proteins by gevokizumab may have to be evaluated in terms of potential therapeutic protein drug-drug interactions when considering future development and therapeutic uses of this IL-1β neutralizing mAb. %G English %L hal-01616062 %U https://univ-rennes.hal.science/hal-01616062 %~ UNIV-RENNES1 %~ UNIV-ANGERS %~ IFR140 %~ GIP-BE %~ IRSET %~ STATS-UR1 %~ IRSET-SMS %~ IRSET-CCII %~ IRSET-TREC %~ IRSET-HIAEC %~ IRSET-SMLF %~ IRSET-ERD %~ IRSET-VCER %~ IRSET-NEED %~ IRSET-TNGC %~ UR1-UFR-SVE %~ UR1-HAL %~ UR1-SDV %~ IRSET-1 %~ TEST-UNIV-RENNES %~ TEST-UR-CSS %~ UNIV-RENNES %~ UR1-BIO-SA %~ TEST3-HALCNRS