Effect of Gevokizumab on Interleukin-1 beta-Mediated Cytochrome P450 3A4 and Drug Transporter Repression in Cultured Human Hepatocytes

Abstract : 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.
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European Journal of Drug Metabolism and Pharmacokinetics, 2017, 42 (5), pp.871-878. 〈10.1007/s13318-017-0406-1〉
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616062
Contributeur : Xavier Chard-Hutchinson <>
Soumis le : vendredi 13 octobre 2017 - 09:52:10
Dernière modification le : jeudi 21 décembre 2017 - 13:28:03

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Amelie Moreau, Marc Le Vee, Elodie Jouan, Claire Denizot, Yannick Parmentier, et al.. Effect of Gevokizumab on Interleukin-1 beta-Mediated Cytochrome P450 3A4 and Drug Transporter Repression in Cultured Human Hepatocytes. European Journal of Drug Metabolism and Pharmacokinetics, 2017, 42 (5), pp.871-878. 〈10.1007/s13318-017-0406-1〉. 〈hal-01616062〉

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