Pharmacokinetic Studies of 3-Methyl-1-phenyl-2-pyrazolin-5-one(MCI-186) in Rats. (1). Blood and Plasma Levels, Distribution, Metabolism and Excretion after a Single Intravenous Administration.

Komatsu, Teiko; Nakai, Hiroshi; Masaki, Katsuyoshi; Obata, Rie; Nakai, Keiko; Iida, Seiu

doi:10.2133/dmpk.11.463

Cited by 8 publications

(9 citation statements)

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“…Similar uptake and retention of radioactivity in aorta tissue was reported in a biodistribution study of rats injected with 14 C-labeled edaravone by Komatsu et al, 36) in which it was proposed as a chemical trap for 14 Clabeled edaravone with free radical species existing in this tissue, although it is largely speculation in the absence of detailed studies. Thus, from the tissue biodistribution in normal mice, a general clearance of the radioactivity over time in all organs was found, qualitatively similar to that seen with 14 Clabeled edaravone in rats, 23) in spite of the large differences in specific activities of these agents.…”

Section: Resultssupporting

confidence: 67%

“…18,19) Biochemical and chemical studies have found that the free radical scavenging reaction of edaravone (1) with free radical species produces mainly 2-oxo-3-(phenylhydrazono)butanoic acid (OPB) with a more hydrophilic character as a stable oxidative product. 17,20,21) In addition, metabolite studies have indicated that edaravone, after intravenous administration in rats and humans, is exclusively metabolized into its glucuronide and/or sulfate conjugates which are excreted into the urine via the kidney, 22,23) except for oxidation process according to its radical scavenging functions. Such in vivo behavior of edaravone thus appeared to have favorable properties as a lead molecule for the development of radiotracers of the metabolic trapping type suitable for detecting free radicals in vivo.…”

Section: -5)mentioning

confidence: 99%

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1-(3'-[125I]Iodophenyl)-3-methy-2-pyrazolin-5-one: Preparation, Solution Stability, and Biodistribution in Normal Mice

et al. 2010

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Recent studies indicate that reactive oxygen species (ROS), such as hydroxyl radical and hydrogen peroxide, are generated in a normal physiological process, and that the imbalance between the antioxidant defense system and excessive levels of ROS in cellular systems is involved in the initiation and progression of various diseases and disorders. [1][2][3][4][5] Various chemical probes of several methods have been developed to measure ROS in biological systems and the most common approach is the measurement of the levels of trapped molecules formed as a result of interception of ROS by probe molecules.6,7) Potential problems in detection and quantification of ROS by methods currently available have been reviewed, 8,9) in which the difficulties of precisely analyzing ROS-expression in the whole body are discussed, because of the low concentration of ROS formed in tissues and interference by the presence of endogenous reductants. Nevertheless, in vivo imaging technologies that allow visualization of localized production and accumulation of ROS in a living system provide useful information on the pathophysiological status of the living body, and they have attracted a great deal of interest.Of several biological imaging methods, nuclear imaging technology, such as positron emission tomography or single photon emission computed tomography using radiolabeled molecules, is well known for its ability to assess molecular pathways in vivo in both pre-clinical and clinical studies with very high sensitivity.10) The first reported work in developing radiotracers for free radical imaging in vivo includes 125 Ilabeled analogs of a-p-hydroxy-m-iodophenyl-N-t-butylnitrone 11) and a-p-iodophenyl-N-tert-butyl-nitrone, 12) based on the chemical characteristic that free radicals can be reacted with nitrone-based compounds at the nitrone-double bond to form organic radical adducts, but none of these proved to be useful as in vivo probes because of their limited free radical specificity. An 18 F-labeled analog of N-t-butylnitrone 13) or ethylmethylthiourea compound 14) has also been prepared, but with no information on its in vivo behavior. Thus, no appropriate radiotracers for nuclear imaging technology are currently available for detecting free radicals in vivo.3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1, Fig. 1), known as a potent free radical scavenger, has been used clinically for the treatment of cerebral infarction in humans to prevent ischemic reperfusion injury [15][16][17] and has also been reported to be effective for myocardial and hepatic ischemia as well. 18,19) Biochemical and chemical studies have found that the free radical scavenging reaction of edaravone (1) with free radical species produces mainly 2-oxo-3-(phenylhydrazono)butanoic acid (OPB) with a more hydrophilic character as a stable oxidative product. 17,20,21) In addition, metabolite studies have indicated that edaravone, after intravenous administration in rats and humans, is exclusively metabolized into its glucuronide and/or sulfate conjugates which...

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Section: Resultssupporting

confidence: 67%

Section: -5)mentioning

confidence: 99%

1-(3'-[125I]Iodophenyl)-3-methy-2-pyrazolin-5-one: Preparation, Solution Stability, and Biodistribution in Normal Mice

et al. 2010

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“…We were unable to observe any MRP2-dependent transport of edaravone glucuronide in membrane vesicles expressing human MRP2 (data not shown). Edaravone sulfate and glucuronide are barely excreted into the bile in rats although they are formed mainly in the liver (Komatsu et al, 1996). Therefore, Mrp2 may not be involved in the tubular secretion of edaravone glucuronide.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Role of Breast Cancer Resistance Protein (BCRP/ABCG2) and Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) in The Urinary Excretion of Sulfate and Glucuronide Metabolites of Edaravone (MCI-186; 3-Methyl-1-phenyl-2-pyrazolin-5-one)

Mizuno¹,

Takahashi²,

Kusuhara³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the treatment of acute cerebral infarction. Edaravone is mainly excreted into the urine after conjugation to glucuronide or sulfate. Previous studies have demonstrated that edaravone sulfate is a good substrate of human organic anion transporter (OAT) 1 (SLC22A6) and human OAT3 (SLC22A8). In this study, we examined the involvement of breast cancer resistance protein [BCRP (ABCG2)] and [multidrug resistance-associated protein 4 MRP4 (ABCC4)] in the luminal efflux in the kidney. Increased ATP-dependent uptake of edaravone sulfate but not edaravone glucuronide was observed in BCRP-expressing membrane vesicles compared with control vesicles (K m ‫؍‬ 16.5 M). In contrast, edaravone glucuronide, but not edaravone sulfate, exhibited greater ATP-dependent uptake in MRP4-expressing membrane vesicles than that in control vesicles (K m ‫؍‬ 9.85 M). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of edaravone glucuronide by MRP4. The functional importance of BCRP and MRP4 in the urinary excretion of edaravone sulfate and edaravone glucuronide, respectively, was investigated using Bcrp and Mrp4 knockout mice. The renal clearance with respect to the kidney concentration of edaravone sulfate was reduced significantly but not abolished in Bcrp knockout mice compared with wild-type mice (3.62 versus 4.85 ml/min/kg b.wt.). The renal clearance of edaravone glucuronide was lower in Mrp4 knockout mice than wild-type mice (2.01 versus 5.06 ml/min/kg BW). Our results suggest that Bcrp and Mrp4 are partly involved in the luminal efflux of edaravone sulfate and edaravone glucuronide, respectively.

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“…These results suggest the possibility of transdermal and transmucosal treatment with edaravone. On the other hand, it has been reported that the pharmacokinetics of edaravone after intravenous administration in rats 8) and humans 9) involve excretion of glucuronide and sulfate. Moreover, the activity of UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) in human skin has also been reported.…”

Section: )mentioning

confidence: 99%

“…To compare HPLC of edaravone in Wistar and hairless rat skin homogenate supernatant fluids, the mobile phase consisted of a mixture of methanol : 10 mmol sodium acetate (35 : 65, v/v, pH 5.5, adjusted with 10% acetic acid), 8) and the flow rate of the mobile phase was 0.5 ml/min.…”

Section: Comparison Of Hplc Of Edaravone In Wistar and Hairless Rat Smentioning

confidence: 99%

In Vitro Metabolism Study of Edaravone in Wistar and Hairless Rat Skin

Sato

Mizuno

Ishii

2008

Biological & Pharmaceutical Bulletin

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3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone, Radicut injection) acts as an antioxidative radical scavenger, and has been developed as a treatment for cerebrovascular disease. 1)In addition, edaravone has been reported to have protective effects on functional damage caused by hyperglycemia to human dermal microvascular endothelial cells, 2) inflammation-induced pain 3) and cisplatin-induced nephrotoxicity in rats. 4) There are also many reports that edaravone has a protective effect on ischemic diseases caused by oxidative stress. Edaravone administration in patients with rheumatoid arthritis leads to a reduction in serum C-reactive protein and disease activity score. 5) Therefore, edaravone is expected to have a role in the prevention and treatment of acute and chronic diseases.Transdermal absorption can be considered as an administration route for prolonged edaravone action. We have already reported the formation of an edaravone/cyclodextrin complex 6) and its skin permeability.7) It has previously been clearly shown that the edaravone/cyclodextrin complex increases the amount of edaravone on the skin surface, as well as its skin permeability. These results suggest the possibility of transdermal and transmucosal treatment with edaravone. On the other hand, it has been reported that the pharmacokinetics of edaravone after intravenous administration in rats 8) and humans 9) involve excretion of glucuronide and sulfate. Moreover, the activity of UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) in human skin has also been reported. [10][11][12] Therefore, it is considered that skin metabolism of edaravone in humans may be similar to that in rat skin. However, there have been no reports on skin metabolism of edaravone.In this study, we used Wistar and hairless rat skin to investigate the metabolism of edaravone in vitro. MATERIALS AND METHODS MaterialsEdaravone was synthesized from ethyl acetoacetate and phenylphydrazine according to the method of Komatu et al. 13) All other reagents and solvents were of special grade and used without further purification.Animals Wistar/ST and hairless (HWY) male rats were obtained from Japan SLC (Shizuoka, Japan). These animals were housed in rooms controlled at 23Ϯ2°C and 55Ϯ15% relative humidity. Pelleted chow (Certified Rodent Diet #002; PMI Nutriton International, U.S.A.) and water were given ad libitum. 10-and 24-Week-old Wistar rats and 10-week-old hairless rats were used for experiments. All experiments were performed under the regulations of the Animal Ethical Committee of Mikasa Seiyaku (based on the Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Science and Technology).Residual Edaravone in Skin Homogenate and Intact Skin One gram of abdominal skin was excised from three or four 10-and 24-week-old Wistar or 10-week-old hairless rats, homogenized in 10 ml saline (Physcotron NS-50; Microtec, Chiba, Japan), and centrifuged a...

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Pharmacokinetic Studies of 3-Methyl-1-phenyl-2-pyrazolin-5-one(MCI-186) in Rats. (1). Blood and Plasma Levels, Distribution, Metabolism and Excretion after a Single Intravenous Administration.

Cited by 8 publications

References 6 publications

1-(3'-[125I]Iodophenyl)-3-methy-2-pyrazolin-5-one: Preparation, Solution Stability, and Biodistribution in Normal Mice

1-(3'-[125I]Iodophenyl)-3-methy-2-pyrazolin-5-one: Preparation, Solution Stability, and Biodistribution in Normal Mice

Evaluation of the Role of Breast Cancer Resistance Protein (BCRP/ABCG2) and Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) in The Urinary Excretion of Sulfate and Glucuronide Metabolites of Edaravone (MCI-186; 3-Methyl-1-phenyl-2-pyrazolin-5-one)

In Vitro Metabolism Study of Edaravone in Wistar and Hairless Rat Skin

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