Malik Paul, Mian Paola, Andrews Jinsy, Rosebraugh Matthew, Ajroud-Driss Senda
Ionis Pharmaceuticals, Carlsbad, California, USA.
University Medical Center Groningen and University of Groningen, Groningen, the Netherlands.
Clin Transl Sci. 2025 Sep;18(9):e70358. doi: 10.1111/cts.70358.
Cytochrome-P-450 (CYP)1A2 has been considered the major enzyme metabolizing riluzole since its approval. However, the inhibitor that was used in the original experiments, α-naphthoflavone, is also a potent inhibitor of CYP1A1. In this work, physiologically based pharmacokinetic (PBPK) modeling investigates the interplay between CYP1A1 and CYP1A2 and the relevance to drug-drug interactions. Following review of clinical and non-clinical data from literature, the relative contributions of CYP1A1, CYP1A2, and UGT1A8/9 to riluzole metabolism were assigned as 60%, 30%, and 10%, respectively. The model was calibrated on single-dose pharmacokinetic (PK) data from healthy subjects. The translational potential of the model was verified by predicting riluzole PK in people with amyotrophic lateral sclerosis, spinal muscular atrophy, advanced age, renal impairment, and hepatic impairment, and when administered with a high-fat meal. The relative contributions of CYP1A1 and CYP1A2 to metabolism were verified through prediction of an observed drug-drug interaction between riluzole and fluvoxamine-a strong CYP1A2 inhibitor and a weak CYP1A1 inhibitor-in children with obsessive-compulsive disorder. Overall, evidence suggests that CYP1A1 is a major enzyme metabolizing riluzole, and that CYP1A2 has similar or lower importance. Only clinically relevant inhibitors of both enzymes may pose a safety concern when administered with riluzole. Strong CYP1A1 inhibitors and strong CYP1A2 inhibitors may be used with caution if they do not significantly modulate the other enzyme. Concomitant use of CYP1A1 inducers may be reconsidered where possible. The enzymatic contributions to riluzole metabolism should be reconsidered after formal drug-drug interaction studies are completed.
自获批以来，细胞色素P - 450（CYP）1A2一直被认为是代谢利鲁唑的主要酶。然而，最初实验中使用的抑制剂α - 萘黄酮也是CYP1A1的强效抑制剂。在这项研究中，基于生理的药代动力学（PBPK）模型研究了CYP1A1和CYP1A2之间的相互作用以及与药物 - 药物相互作用的相关性。在回顾文献中的临床和非临床数据后，将CYP1A1、CYP1A2和UGT1A8/9对利鲁唑代谢的相对贡献分别设定为60%、30%和10%。该模型根据健康受试者的单剂量药代动力学（PK）数据进行校准。通过预测肌萎缩侧索硬化症、脊髓性肌萎缩症、老年、肾功能损害和肝功能损害患者以及高脂饮食时服用利鲁唑后的PK，验证了该模型的转化潜力。通过预测利鲁唑与氟伏沙明（一种强效CYP1A2抑制剂和弱效CYP1A1抑制剂）在强迫症儿童中的药物 - 药物相互作用，验证了CYP1A1和CYP1A2对代谢的相对贡献。总体而言，有证据表明CYP1A1是代谢利鲁唑的主要酶，而CYP1A2的重要性相似或更低。只有两种酶的临床相关抑制剂与利鲁唑合用时可能会引起安全问题。强效CYP1A1抑制剂和强效CYP1A2抑制剂如果对另一种酶没有显著调节作用，可以谨慎使用。如果可能，应重新考虑同时使用CYP1A1诱导剂。在完成正式的药物 - 药物相互作用研究后，应重新考虑酶对利鲁唑代谢的贡献。
