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Research ArticleArticle

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)

Naomi Mizuno, Tsuyoshi Takahashi, Hiroyuki Kusuhara, John D. Schuetz, Takuro Niwa and Yuichi Sugiyama
Drug Metabolism and Disposition November 2007, 35 (11) 2045-2052; DOI: https://doi.org/10.1124/dmd.107.016352
Naomi Mizuno
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Tsuyoshi Takahashi
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Hiroyuki Kusuhara
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John D. Schuetz
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Takuro Niwa
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Yuichi Sugiyama
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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 (Km = 16.5 μM). In contrast, edaravone glucuronide, but not edaravone sulfate, exhibited greater ATP-dependent uptake in MRP4-expressing membrane vesicles than that in control vesicles (Km = 9.85 μM). 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.

Footnotes

  • doi:10.1124/dmd.107.016352.

  • ABBREVIATIONS: GFR, glomerular filtration rate; OAT, organic anion transporter; BBM, brush border membrane; ABC, ATP-binding cassette; MRP (Mrp), multidrug resistance associated protein; BCRP (Bcrp), breast cancer resistance protein; DHEAS, dehydroepiandrosterone sulfate; E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole; MCI-186, methyl-1-phenyl-2-pyrazolin-5-one, edaravone;4′-Me-MCI-186, 3-methyl-1-(4-methyl-phenyl)-pyrazolin-5-one; 13C4-MCI-186, 3-[13C]methyl-1-phenyl-2-[3,4,5-13C]-pyrazolin-5-one; HPLC, high-performance liquid chromatography; E1S, estrone 3-sulfate; HEK, human embryonic kidney; GFP, green fluorescent fusion protein; h, human; 4-MU, 4-methylumbelliferone.

    • Received May 16, 2007.
    • Accepted August 1, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (11)
Drug Metabolism and Disposition
Vol. 35, Issue 11
1 Nov 2007
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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)
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Research ArticleArticle

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)

Naomi Mizuno, Tsuyoshi Takahashi, Hiroyuki Kusuhara, John D. Schuetz, Takuro Niwa and Yuichi Sugiyama
Drug Metabolism and Disposition November 1, 2007, 35 (11) 2045-2052; DOI: https://doi.org/10.1124/dmd.107.016352

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Research ArticleArticle

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)

Naomi Mizuno, Tsuyoshi Takahashi, Hiroyuki Kusuhara, John D. Schuetz, Takuro Niwa and Yuichi Sugiyama
Drug Metabolism and Disposition November 1, 2007, 35 (11) 2045-2052; DOI: https://doi.org/10.1124/dmd.107.016352
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