Identification of the primary determining factor(s) governing the oral absorption of edaravone in rats

Hyung, Sungwoo; Jeong, Yonghwan; Yeo, Jungmin; Song, YoungGoo; Kim, Min-Soo; Im, Young Jae; Maeng, Han Joo; Chung, Suk Jae

doi:10.1016/j.ejps.2018.07.052

Cited by 9 publications

(5 citation statements)

References 44 publications

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“…If both edaravone and TEJ-1704 follow linear pharmacokinetics in rats, the absolute bioavailability was calculated to be 75.22% for edaravone-administered group (calculated from group R1 and R2) and 46.10% for TEJ-1704-administered group (calculated from group R3 and R4). The absolute bioavailability calculated from edaravone-administered groups concurred with the previous report [ 17 ] that manifested high absolute bioavailability (50–90%) at dose ranges of 0.5 to 27 mg/kg. However, since the absolute bioavailability of edaravone in the TEJ-1704-administered group was lower than the value reported in the literature, a dose adjustment of the prodrug is needed.…”

Section: Resultssupporting

confidence: 90%

Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704

Kang

Kim

et al. 2021

Pharmaceutics

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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 Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, 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.

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Section: Resultssupporting

confidence: 90%

Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704

Kang

Kim

et al. 2021

Pharmaceutics

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“…The P-gp overexpression over the course of the disease may explain the poor bioavailability of riluzole within CNS parenchyma thereby limiting its therapeutic efficacy (Milane et al, 2010 ; Jablonski et al, 2014 ). In contrast, edavarone, a free radical scavenger approved for ALS treatment, has negligible P-gp binding and is potentially less influenced by BCNSB efflux activity (Dash et al, 2018 ; Hyung et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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IntroductionRecent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.MethodsA literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.ResultsThe search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.ConclusionBCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.

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“…However, the applicability of edaravone in cancer treatment shows some limitations. Major concerns are its extremely low aqueous solubility and limited bioavailability, which hamper its intestinal absorption and necessitate the use of high-dose parenteral administration [157]. This route of drug delivery can be challenging for cancer patients, whereas oral administration would be preferable and may help to improve patients' quality of life by avoiding infusion-related stress, the risk of infusion-related infections or extravasations, infusion-related discomfort, and the need for further administration visits.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Edaravone: A Novel Possible Drug for Cancer Treatment?

Duranti,

Cordani,

Villa

2024

IJMS

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Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.

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Identification of the primary determining factor(s) governing the oral absorption of edaravone in rats

Cited by 9 publications

References 44 publications

Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704

Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Edaravone: A Novel Possible Drug for Cancer Treatment?

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