Moreau Amélie, Le Vée Marc, Jouan Elodie, Denizot Claire, Parmentier Yannick, Fardel Olivier
Centre de Recherche en Pharmacocinétique, Technologie Servier, Orléans, France.
Institut de Recherches en Santé, Environnement et Travail (IRSET) UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 34043, Rennes, France.
Eur J Drug Metab Pharmacokinet. 2017 Oct;42(5):871-878. doi: 10.1007/s13318-017-0406-1.
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.
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.
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).
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.
gevokizumab是一种有效的抗白细胞介素（IL）-1β中和单克隆抗体（mAb），可用于治疗炎症性或自身免疫性疾病。本研究旨在表征该单克隆抗体对已确定的IL-1β介导的肝脏药物解毒蛋白（如细胞色素P450（CYP）3A4和药物转运体）抑制作用的潜在影响。
将原代培养的人肝细胞在不存在或存在gevokizumab（5μg/mL）的情况下暴露于不同浓度的IL-1β；接下来测定CYP3A4和转运体的mRNA表达及活性。
发现gevokizumab通过将IL-1β半数最大抑制浓度（IC）值提高6.8至10.4倍，下调但未消除人肝细胞中由IL-1β引起的CYP3A4和药物转运体mRNA的抑制。该单克隆抗体同时将IL-1β对CYP3A4活性的IC值从22.0 pg/mL（不存在gevokizumab时）转变为796 pg/mL（存在gevokizumab时），并抵消了响应50 pg/mL IL-1β时发生的有机阴离子转运多肽活性的降低，但未抵消在更高IL-1β浓度（1000 pg/mL）时发生的降低。
gevokizumab减弱但未消除人肝细胞中IL-1β介导的CYP3A4和药物转运体的功能抑制，这与该单克隆抗体被认为是IL-1β信号的调节剂而非阻断剂这一事实相符。在考虑这种IL-1β中和单克隆抗体的未来开发和治疗用途时，可能必须根据潜在的治疗性蛋白质药物相互作用来评估gevokizumab对IL-1β介导的肝脏解毒蛋白下调的这种减弱作用。
