title: Effect of Gevokizumab on Interleukin-1β-Mediated Cytochrome P450 3A4 and Drug Transporter Repression in Cultured Human Hepatocytes.
abstract: OBJECTIVE
  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 (IC50) values by factors ranging from 6.8 to 10.4. The mAb concomitantly shifted IL-1β IC50values 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre de Recherche en Pharmacocinétique, Technologie Servier, Orléans, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Moreau
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET) UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 34043, Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vée
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET) UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 34043, Rennes, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouan
authors.affiliation: Centre de Recherche en Pharmacocinétique, Technologie Servier, Orléans, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Denizot
authors.affiliation: Centre de Recherche en Pharmacocinétique, Technologie Servier, Orléans, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Parmentier
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET) UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 34043, Rennes, France. olivier.fardel@univ-rennes1.fr.|Pôle Biologie, Centre Hospitalier Universitaire, Rennes, France. olivier.fardel@univ-rennes1.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053583:Interleukin-1beta; D027361:Organic Anion Transporters; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C547697:gevokizumab
keywords: Denosumab; Drug Transporter; Human Hepatocyte; Probenecid; Tocilizumab