Pharmacokinetic Studies of 3-Methyl-1-phenyl-2-pyrazolin-5-one(MCI-186): Metabolism in Rats, Dogs and Human.

Komatsu, Teiko; Nakai, Hiroshi; Takamatsu, Yasuo; Morinaka, Yasuhiro; Watanabe, Kazutoshi; Shinoda, Masaki; Iida, Seiu

doi:10.2133/dmpk.11.451

Cited by 15 publications

(19 citation statements)

References 7 publications

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“…In the case of rats or dogs, the main metabolite in both urine and plasma was the sulfate (Komatsu et al, 1996). An in vitro study using human kidney S9 has suggested that edaravone sulfate undergoes conversion to edaravone by sulfatase, followed by glucuronidation in the human kidney (Yokota et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Human Organic Anion Transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) Transport Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and Its Sulfate Conjugate

Mizuno¹,

Takahashi²,

Iwase³

et al. 2007

Drug Metab Dispos

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ABSTRACT:3-Methyl-1-phenyl-2-pyrazolin-5-one (MCI-186; edaravone), a novel free radical scavenger, is used for the treatment of acute cerebral infarction. After marketing, a few cases of acute renal failure were reported in patients following treatment with this drug. Because edaravone is mainly excreted into the urine following conjugation to glucuronide or sulfate, the renal excretion mechanisms of edaravone should help provide important information when considering the clinical cases. We examined the transport of edaravone and its sulfate and glucuronide conjugates via human organic anion transporter 1 (hOAT1) and 3 (hOAT3), expressed on the basolateral membranes of proximal tubules. The hOAT1-and hOAT3-transfected human embryonic kidney (HEK)-293 cells exhibited a markedly higher uptake of edaravone sulfate and a slightly higher uptake of edaravone than vector-transfected cells. The K m values of edaravone sulfate uptake by hOAT1 and hOAT3 were 11 and 15 M, respectively. Estimation of the relative contribution of hOAT1 and hOAT3 using reference compounds suggested that hOAT1 and hOAT3 might contribute to the renal uptake of edaravone sulfate to the same extent. However, edaravone and its sulfate showed no cytotoxicity toward both hOAT1-HEK and control cells, suggesting that higher uptake in hOAT1-HEK did not associate with cytotoxicity of these compounds. In conclusion, our results suggest that both hOAT1 and hOAT3 are responsible for the basolateral uptake of edaravone sulfate in the kidney.

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Section: Discussionmentioning

confidence: 99%

Human Organic Anion Transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) Transport Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and Its Sulfate Conjugate

Mizuno¹,

Takahashi²,

Iwase³

et al. 2007

Drug Metab Dispos

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“…In rats and dogs, urinary excretion rates of sulfate were higher than those of glucuronide, whereas in human urine, glucuronide was excreted more than sulfate (Komatsu et al, 1996). This species difference may be due to differential expression of UGT1A9 in kidneys of these species.…”

Section: Glucuronidation Of Edaravone By Hlm and Hkmmentioning

confidence: 93%

“…Pharmacokinetic studies showed that edaravone was mainly eliminated as glucuronide conjugate (approximately 70%; Fig. 1B) in humans (Komatsu et al, 1996;Yokota et al, 1997;Shibata et al, 1998). However, no detailed data were available about UDP-glucuronosyltransferase (UGT) isoforms involved in edaravone glucuronidation.…”

Section: Introductionmentioning

confidence: 99%

Glucuronidation of Edaravone by Human Liver and Kidney Microsomes: Biphasic Kinetics and Identification of UGT1A9 as the Major UDP-Glucuronosyltransferase Isoform

Ma¹,

Sun²,

Peng³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Edaravone was launched in Japan in 2001 and was the first neuroprotectant developed for the treatment of acute cerebral infarction. Edaravone is mainly eliminated as glucuronide conjugate in human urine (approximately 70%), but the mechanism involved in the elimination pathway remains unidentified. We investigated the glucuronidation of edaravone in human liver microsomes (HLM) and human kidney microsomes (HKM) and identified the major hepatic and renal UDP-glucuronosyltransferases (UGTs) involved. As we observed, edaravone glucuronidation in HLM and HKM exhibited biphasic kinetics. The intrinsic clearance of glucuronidation at high-affinity phase (CL int1 ) and low-affinity phase (CL int2 ) were 8. , respectively, for HLM and were 78.5 ؎ 3.9 and 3.6 ؎ 0.5 l ⅐ min ؊1 ⅐ mg ؊1, respectively, for HKM. Screening with 12 recombinant UGTs indicated that eight UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17) produced a significant amount of glucuronide metabolite. Thus, six UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A9, UGT2B7, and UGT2B17) expressed in human liver or kidney were selected for kinetic studies. Among them, UGT1A9 exhibited the highest activity (CL int1 ‫؍‬ 42.4 ؎ 9.5 l ⅐ min ؊1 ⅐ mg

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“…Edaravone 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.…”

Section: Methodsmentioning

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): Metabolism in Rats, Dogs and Human.

Cited by 15 publications

References 7 publications

Human Organic Anion Transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) Transport Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and Its Sulfate Conjugate

Human Organic Anion Transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) Transport Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and Its Sulfate Conjugate

Glucuronidation of Edaravone by Human Liver and Kidney Microsomes: Biphasic Kinetics and Identification of UGT1A9 as the Major UDP-Glucuronosyltransferase Isoform

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

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