抗アレルギー薬1-(2-Ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-benzimidazole Difumarate(KG-2413)のラジオレセプターアッセイにおける活性代謝物の交差性
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概要
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A new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413), was orally administered to guinea pigs at a dose of 2 mg/kg. The drug levels in the plasma measured by the radioreceptor assay (RRA) method were significantly higher by 7% than those by the gas chromatographic (GC) method which was selective for the intact drug. Among the metabolites of KG-2413,1-(2-ethoxyethyl)-2-(hexahydro-1H-1,4-diazepin-1-yl)-1H-benzimidazole (desmethyl metabolite) and 1-(2-ethoxyethyl)-5-hydroxy-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-benzimidazole (5-hydroxy metabolite) had relatively high cross-reactivities of 29% and 21%, respectively, on the RRA method. However, the 5-hydroxy metabolite was not extracted with benzene under strongly basic conditions on the extraction procedure carried out prior to the receptor assay. Therefore, it was suggested that the desmethyl metabolite might affect the RRA method. In order to determine the amount of the desmethyl metabolite in the plasma, a high-performance liquid chromatographic method was established to determine the dansyl derivative of the desmethyl metabolite. By using this method, it was found that the desmethyl metabolite corresponding to 21-32% of the intact drug was present in the plasma after oral administration of KG-2413 at a dose of 2 mg/kg. Taking account of the cross-reactivity (29%) and extraction ratio (83%) of the desmethyl metabolite, this active metabolite affects the RRA method to give 5.1-7.7% overestimation of the intact drug concentration. Therefore, it became clear that the presence of the active desmethyl metabolite resulted in the difference between the GC and RRA method.
- 公益社団法人日本薬学会の論文
- 1989-07-25
著者
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川島 恒男
千葉大学薬学部
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粟田 則男
鐘紡株式会社薬品開発研究所
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粟田 則男
Department Of Formulation Research Pharmaceuticals Research Center Kanebo Ltd.
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粟田 則男
鐘紡株式会社 薬品開発第一研究所
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粟田 則男
Product Research And Development Laboratories Pharmaceuticals Research Center Kanebo Ltd.
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粟田 則男
鐘紡株式会社薬品研究所
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浜田 司
鐘紡株式会社薬品研究所
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川島 恒男
鐘紡株式会社薬品開発研究所
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