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<datestamp>2017-12-21</datestamp>
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<publisher>HAL CCSD</publisher>
<title lang=en>Effect of Gevokizumab on Interleukin-1 beta-Mediated Cytochrome P450 3A4 and Drug Transporter Repression in Cultured Human Hepatocytes</title>
<creator>Moreau, Amelie</creator>
<creator>Le Vee, Marc</creator>
<creator>Jouan, Elodie</creator>
<creator>Denizot, Claire</creator>
<creator>Parmentier, Yannick</creator>
<creator>FARDEL, Olivier</creator>
<contributor>Technologie Servier ; Technologie Servier</contributor>
<contributor>Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )</contributor>
<description>International audience</description>
<source>ISSN: 0378-7966</source>
<source>EISSN: 2107-0180</source>
<source>European Journal of Drug Metabolism and Pharmacokinetics</source>
<identifier>hal-01616062</identifier>
<identifier>https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616062</identifier>
<source>https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616062</source>
<source>European Journal of Drug Metabolism and Pharmacokinetics, 2017, 42 (5), pp.871-878. 〈10.1007/s13318-017-0406-1〉</source>
<identifier>DOI : 10.1007/s13318-017-0406-1</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.1007/s13318-017-0406-1</relation>
<language>en</language>
<subject>[SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health</subject>
<type>info:eu-repo/semantics/article</type>
<type>Journal articles</type>
<description lang=en>Gevokizumab is a potent anti-interleukin (IL)-1 beta 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-1 beta-mediated repression of hepatic drug detoxifying proteins, like cytochrome P450 (CYP) 3A4 and drug transporters. Primary cultured human hepatocytes were exposed to various concentrations of IL-1 beta in the absence or presence of gevokizumab (5 A mu g/mL); mRNA expression and activity of CYP3A4 and transporters were next determined. Gevokizumab was found to down-modulate, but not abolish, the repression of CYP3A4 and drug transporter mRNAs caused by IL-1 beta in human hepatocytes, through shifting up IL-1 beta half maximal inhibitory concentration (IC50) values by factors ranging from 6.8 to 10.4. The mAb concomitantly shifted IL-1 beta IC50 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-1 beta, but not that occurring at higher IL-1 beta concentration (1000 pg/mL). Gevokizumab attenuates, but not abolishes, IL-1 beta-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-1 beta signaling. This attenuation of IL-1 beta-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-1 beta neutralizing mAb.</description>
<date>2017</date>
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