Abstract
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.
Highlights
Sodium metabisulfite (SMB), trichloroacetic acid (TCA), formic acid, DPPH (1,1-diphenyl-2-picrylhydrazyl radical), and quercetin dehydrate were purchased from Sigma-Aldrich
The edaravone-administered group had an increased survival rate in both males and females compared with the vehicle-administered group
A modified analysis method developed for the quantitation of edaravone in rat and beagle dog matrices after PO or IV administration of edaravone or TEJ-1704 was validated and successfully applied to pharmacokinetic, distribution, and excretion studies of TEJ-1704
Summary
Amyotrophic lateral sclerosis (ALS) is a disorder that causes degeneration of cerebral and spinal cord motor neurons. Its disease progression rate greatly differs depending on individuals, death occurs within 3–5 years after its diagnosis without ventilator support [1]. The underlying cause of ALS remains unclear. Several studies have reported that the concentration of 3-nitrotyrosin (3-NT, a marker of oxidative stress in the spinal cord) and 3-NT immunoreactivity in motor neurons of sporadic and familial ALS patients are increased, suggesting that oxidative stress is an essential factor associated with ALS [2]
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