5-Methyl-2-phenyl-1,2-dihydropyrazol-3-one

Absorption

One study investigated the absorption of edaravone in healthy adults, who either received a single oral (105 mg/mL) or intravenous (60 mg/60 min) dose. The mean Cmax (CV%) and Tmax were 1656 (44.3) ng/mL and 0.5 hours, respectively, following oral administration. The absolute oral bioavailability is about 57% because of first-pass metabolism.
The mean Cmax (CV%) and Tmax were 1253 (18.3) ng/mL and one hour, respectively, following intravenous administration. When intravenously administered, the maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion.
The Cmax and area under the concentration-time curve (AUC) of edaravone increases more than dose-proportional over the dose range of 30 to 300 mg. Edaravone does not accumulate in plasma with once-daily or multiple-dose administration. The Cmax and AUC decreased when the oral suspension formulation of edaravone was administered with a high-fat meal.

Toxicity

Oral and intravenous LD50 in rats are 1915 mg/kg and 631 mg/kg, respectively. There is limited information on the acute toxicity of edaravone.

Description

Edaravone was marketed in Japan for improving neurologic recovery following acute brain infarction. Currently, several agents classified as neuroprotectants and acting by diverse mechanisms (inhibition of glutamate release, blockade of calcium channels, lazaroids) have been marketed for treating the outcomes of brain damage due to trauma, ischemia or cardiac arrest. Edavarone is the first antioxidant with free radical scavenging activity to be introduced for this pathology. This previously described molecule (in particular as norantipyrine, one of three metabolites of antipyrine in mammals) can be simply prepared by direct cyclization of phenylhydrazine with alkylacetoacetate. Edarevone is a lipophilic agent, readily accessible to brain tissue, that is capable of reducing edema in the brain following ischemia by blocking the arachidonic acid cascade triggering peroxidative neurodegeneration. Interestingly, this agent has been shown to quench active oxygen species in endothelial cell homogenate, as well as inhibiting in vitro lipid peroxidative disintegration of membranes, so making this compound effective during reperfusion following ischemic injury. As an additional indication, phase III trials started with edaravone for increasing the chance of recovery after subarachnoid hemorrhage.

The Uses of 5-Methyl-2-phenyl-1,2-dihydropyrazol-3-one

Edaravone inhibits the disease activity in rheumatoid arthritis.

Indications

Edaravone is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in the US and Canada. It is also indicated to treat acute ischemic stroke in Japan.

Background

Edaravone is a free radical scavenger and neuroprotective agent with antioxidant properties. It has three tautomers. Edaravone works to scavenge reactive oxygen species, which have been implicated in neurological disorders, such as amyotrophic lateral sclerosis (ALS) and cerebral ischemia.
The intravenous formulation of edaravone was first approved in Japan in 2001 for the treatment of acute ischemic stroke. It was later approved for the treatment of amyotrophic lateral sclerosis (ALS) in Japan and South Korea in 2015, followed by the FDA approval in May 2017 and Health Canada approval in October 2018. The oral suspension formulation of edaravone was approved by the FDA in May 2022 and by Health Canada in November 2022.
Edaravone was initially granted orphan designation by the European Medicines Agency on June 19, 2015 and was under regulatory review in Europe. However, the drug manufacturer, Mitsubishi Tanabe Pharma, withdrew the Marketing Authorization Application (MAA) for edaravone from the European market on May 24, 2019, in response to the request made by the Committee for Medicinal Products for Human Use (CHMP) for a long-term study demonstrating the long-term efficacy and safety of edaravone. Edaravone was also investigated in other disorders, such as Alzheimer's disease, neuropathic pain, and ischemia-induced nerve injury.

What are the applications of Application

MCI-186 is a free radical scavenger that enhances NGF protein levels via the JNK pathway

Pharmacokinetics

Edaravone works to delay the disease progression of neurological disorders such as ischemic stroke and ALS by limiting the extent of neuronal damage or death.

Metabolism

The metabolites of edaravone have not been fully characterized. Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17). In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases. Oral edaravone results in 1.3- and 1.7-fold higher exposures for both sulfate and glucuronide metabolites, respectively, when compared to intravenously-administered edaravone because of first-pass metabolism.