Metabolism of 4-Ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M73101), a New Anti-inflammatory Agent. I. : Identification of the Metabolites in Rabbit and Their Pharmacological Studies
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概要
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The metabolism of 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M73101) in rabbits and the pharmacological activities of metabolites were investigated. Rabbits orally received the drug in a dose of 100 mg/kg excreted ten metabolites together with unchanged drug in the urine. These metabolites were characterized by their spectrometric data (infrared, mass, ultraviolet, and nuclear magnetic resonance spectra), thin-layer chromatography and gas chromatography. Some of them were unequivocally identified by comparison with synthesized authentic samples. The following compounds were found to be present in the urine : 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (unchanged drug), 4-hydroxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M-1), 5-bis (2-hydroxyethyl) amino-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-2), 4-ethoxy-5-[2-(β-hydroxyethyloxy) ethylamino]-2-methyl-3 (2H)-pyridazinone (M-3), 4-ethoxy-5-(2-hydroxyethylamino)-2-methyl-3 (2H)-pyridazinone (M-4), 4-ethoxy-5-(2-hydroxy-tetrahydro-1,4-oxazin-4-yl)-2-methyl-3 (2H)-pyridazinone (M-5), 4-ethoxy-5-morpholino-3 (2H)-pyridazinone (M-6), 4-ethoxy-2-methyl-5-(3-oxotetrahydro-1,4-oxazin-4-yl)-3 (2H)-pyridazinone (M-7), 5-(N-carboxymethyl-N-2-hydroxyethylamino)-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-8), 5-[2-(carboxymethyloxy)-ethylamino]-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-9), 5-carboxymethylamino-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-10). From these results, it was concluded that the major metabolic route in rabbits was oxidative cleavage of C-N and C-O of morpholino group followed by further degradation. Deethylation and demethylation were found to be minor reaction. In the pharmacologocal studies of metabolites, no activities were observed, which indicated that the pharmacological activities of M73101 were not due to these urinary metabolites.
- 社団法人日本薬学会の論文
- 1978-10-25
著者
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佐藤 誠
Faculty of Pharmaceutical Sciences Toyama Medical and Pharmaceutical University
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大木 正彦
Research Laboratories, Morishita Pharmaceutical Co., Ltd.
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佐藤 誠
Research Institute, Daiichi Seiyaku Co., Ltd.,
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林 敏廣
Research Laboratories Morishita Pharmaceutical Co. Ltd.
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岸川 虎比古
Research Laboratories, Morishita Pharmaceutical Co., Ltd.
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大木 正彦
森下製薬株式会社薬理研究所
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佐藤 誠
森下ルセル株式会社総合研究所
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大木 正彦
Research Laboratories Morishita Pharmaceutical Co. Ltd.
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岸川 虎比古
Research Laboratories Morishita Pharmaceutical Co. Ltd.
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林 敏廣
ヘキスト・マリオン・ルセル(株)医薬情報開発本部 輸液研究部
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