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

European Journal of Drug Metabolism and Pharmacokinetics, ISSN: 2107-0180, Vol: 42, Issue: 5, Page: 871-878
2017
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Article Description

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.

Bibliographic Details

Moreau, Amélie; Le Vée, Marc; Jouan, Elodie; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

Springer Science and Business Media LLC

Pharmacology, Toxicology and Pharmaceutics; Medicine

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