CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; CPIRN-UDI-IPG - Center for Potential and Innovation of Natural Resources, Research Unit for Inland Development, Polytechnic Institute of Guarda, Av. Dr. Francisco de Sá Carneiro, 6300-559 Guarda, Portugal.
Toxicol In Vitro. 2022 Aug;82:105389. doi: 10.1016/j.tiv.2022.105389. Epub 2022 May 18.
New-generation antiepileptic drugs as perampanel, rufinamide and stiripentol emerged as alternatives in chronic epilepsy polytherapy. Hence, their metabolic stability and potential involvement in relevant drug-drug interactions (DDI) are of great clinical interest, being HepaRG cells herein used as an in vitro human model. To characterize their metabolic stability profiles, HepaRG cells were incubated with perampanel (1 μM), rufinamide (100 μM) or stiripentol (5 μM) for 12-h. HepaRG cells, pretreated with known CYP450 isoenzymes inducers (rifampicin, phenytoin, phenobarbital, omeprazole and carbamazepine), were also incubated with perampanel, rufinamide or stiripentol to assess possible DDI mediated by CYP450 induction. Results suggest a considerable decrease in perampanel and stiripentol concentrations over 12-h; contrary, rufinamide concentrations did not variated. Cells pretreatment with all inducers significantly decreased stiripentol concentrations (between 20.3% and 31.9%), suggesting a considerable potential for DDI. Rufinamide concentrations only decreased when preincubated with rifampicin and with the highest tested concentrations of the remaining inducers. Perampanel levels decreased with rifampicin, carbamazepine and phenobarbital, supporting the involvement of CYP3A4-mediated metabolism. Besides relevant information concerning the metabolic stability profile and potential DDIs of the new antiepileptics here studied, it was also reinforced the HepaRG cells suitability as a reliable in vitro model to foresee in vivo metabolism in humans.
新一代抗癫痫药物如吡仑帕奈、鲁非酰胺和司替戊醇已成为慢性癫痫多药治疗的替代药物。因此，它们的代谢稳定性和潜在的相关药物相互作用（DDI）具有重要的临床意义，本研究使用 HepaRG 细胞作为体外人类模型。为了表征它们的代谢稳定性特征，将 HepaRG 细胞与吡仑帕奈（1 μM）、鲁非酰胺（100 μM）或司替戊醇（5 μM）孵育 12 小时。还将用已知的 CYP450 同工酶诱导剂（利福平、苯妥英、苯巴比妥、奥美拉唑和卡马西平）预处理 HepaRG 细胞，然后与吡仑帕奈、鲁非酰胺或司替戊醇孵育，以评估 CYP450 诱导介导的可能的 DDI。结果表明，吡仑帕奈和司替戊醇的浓度在 12 小时内显著下降；相反，鲁非酰胺的浓度没有变化。所有诱导剂预处理的细胞均显著降低了司替戊醇的浓度（在 20.3%至 31.9%之间），表明存在相当大的 DDI 潜力。只有当与利福平预孵育或与其余诱导剂的最高测试浓度孵育时，鲁非酰胺的浓度才会降低。吡仑帕奈的水平随利福平、卡马西平和苯巴比妥降低，支持 CYP3A4 介导的代谢。除了研究中新型抗癫痫药物的代谢稳定性特征和潜在 DDI 的相关信息外，还加强了 HepaRG 细胞作为可靠的体外模型，可预测人类体内代谢的适用性。
