Retention Mechanism of Imidazoles in Connective Tissue. IV. Identification of a Nucleophilic imidazolone Metabolite in Rats
スポンサーリンク
概要
- 論文の詳細を見る
Formation of a nucleophilic 4(5H)(or 5(4H))-imidazolone structure has been postulated from in vitro studies to be one of the causative elements involved in the retention of drugs with imidazole moiety in connective tissue.To confirm this, we searched for the imidazolone-related metabolite in rats after intravenous dosing of 2-methylimidazole (2MI; ^<14>C-labeled and unlabeled form, 3 and 300 μmol/kg body weight) as a model compound.The excreted urine, the major route of elimination of the compound, was collected and analyzed using the HPLC/MS system with a counterion effect for metabolite separation. 2-Methyl-4(5H)(or 5(4H))-imidazolone (2MIone) was identified as a urinary metabolite by chromatographic and mass-spectral inspection with the corresponding authentic standard. Pretreatment of rats with either SKF-525A (50 mg/kg, i.p.) or cimetidine (200 mg/kg, i.p.) significantly increased the excreted amount of 2MIone in urine and the irreversible binding of 2MI equivalents in the aortic tissue, whereas both factors were reduced by pretreatment with triethylenetetramine dihydrochloride (150 mg/kg/d for 5 d, s.c.). These results support the aforementioned deduction, and also raise the possibility that a cytochrome P450-independent, copper-related metabolic reaction might be involved in the imidazolone formation in vivo.
- 公益社団法人日本薬学会の論文
- 1998-12-15
著者
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AWAZU Shoji
Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Science
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Yamaguchi Jun-ichi
Department of Cardiology, Saitama Cardiovascular and Respiratory Center
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SUWA Toshio
Department of Drug Development Science & Clinical Evaluation, Kyoritsu University of Pharmacy
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KOHNO Yoshiro
Department of Drug Metabolism, Medicinal Research Laboratory, Taisho Pharmaceutical Co., Ltd.
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Kohno Yoshiro
大正製薬(株)開発研究所薬物動態研究室
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Kohno Yoshiro
Department Of Drug Metabolism Medicinal Research Laboratory Taisho Pharmaceutical Co. Ltd.
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Yamaguchi Jun-ichi
Department Of Drug Metabolism Taisho Pharmaceutical Research Center
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AWAZU Shoji
東京薬科大学薬学部 薬物動態制御学教室
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Awazu S
Tokyo Coll. Pharmacy Tokyo Jpn
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Awazu Shoji
Department Of Biopharmaceutics Tokyo College Of Pharmacy:department Of Pharmaceutics Research Center
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Suwa T
大正製薬(株)開発研究所薬物動態研究室
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Suwa Toshio
Dept.of Biochemistry Tokyo College Of Pharmacy:(present Address) Research Center Taisho Pharmaceutic
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Ohya Kumiko
Department Of Clinical Pharmacology And Toxicology Showa Pharmaceutical University
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Fukumoto Kyoko
Department Of Pharmacokinetics Kyoto Pharmaceutical University
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Yamaguchi Jun-ichi
Department Of Applied Chemistry Faculty Of Engineering Kanagawa Institute Of Technology
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Awazu Shoji
Deparment Of Biopharmaceutics Tokyo College Of Pharmacy
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OHTA Katsuji
Department of Drug Metabolism, Taisho Pharmaceutical Research Center
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FUKASAWA Yoshiki
Department of Drug Metabolism, Taisho Pharmaceutical Research Center
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FUKUSHIMA Kiyomi
Department of Drug Metabolism, Taisho Pharmaceutical Research Center
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Fukushima K
大正製薬(株)開発研究所薬物動態研究室
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Fukasawa Y
Showa Pharmaceutical Univ. Tokyo Jpn
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Awazu S
Department Of Biopharmaceutics School Of Pharmacy Tokyo University Of Pharmacy And Life Science
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Fukawasa Yoshiki
Department of Drug Metabolism, Taisho Pharmaceutical Research Center
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