Kang Dong Wook, Kim Ju Hee, Kim Kyung Min, Cho Seok-Jin, Jang Hee-Woon, Chang Ji Won, Dong Seung Myung, Lim Jee Woong, Kim Jae-Sun, Cho Hea-Young
College of Pharmacy, CHA University, 335 Pangyo-ro, Seongnam 13488, Korea.
Theragen Etex Co., Ltd., 190 Gangnam-daero, Seoul 06744, Korea.
Pharmaceutics. 2021 Sep 4;13(9):1406. doi: 10.3390/pharmaceutics13091406.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma C of TEJ-1704 was low, groups administered with TEJ-1704 had high AUC, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.
依达拉奉（3 - 甲基 - 1 - 苯基 - 2 - 吡唑啉 - 5 - 酮）是一种被批准用于治疗肌萎缩侧索硬化症（一种致命的神经肌肉疾病）的自由基清除剂。依达拉奉通过静脉输注60分钟给药，进行多个治疗周期。为减轻患者和护理人员的负担，已开发出依达拉奉的口服制剂。本研究的目的是评估依达拉奉口服前体药物TEJ - 1704在雄性斯普拉格 - 道利大鼠和比格犬中的药代动力学和组织分布。使用斯普拉格 - 道利大鼠和比格犬进行动物实验，以评估TEJ - 1704的药代动力学、组织分布和排泄情况。在静脉注射（IV）或口服（PO）依达拉奉或TEJ - 1704后的指定采样时间收集血液、组织、脑脊液、尿液和粪便样本。开发了一种改良的生物分析方法来定量血浆、组织、脑脊液、尿液和粪便等样本中的依达拉奉。该生物分析方法经过验证，并成功应用于新型依达拉奉前体药物的药代动力学、组织分布和排泄研究。尽管TEJ - 1704的血浆C较低，但给予TEJ - 1704的组具有较高的AUC，表明TEJ - 1704持续代谢为依达拉奉。用TEJ - 1704治疗的组与对照组相比，脑脊液分布也较低。给予TEJ - 1704后，大部分依达拉奉分布于心、肺和肾。它通过尿液和粪便等量排泄。成功表征了新型依达拉奉口服前体药物TEJ - 1704的药代动力学、组织分布和排泄情况。需要进一步研究以充分了解TEJ - 1704与依达拉奉之间的差异，并确定TEJ - 1704的效力。
