YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
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
浜田 司川島 恒男粟田 則男
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1989 年 109 巻 7 号 p. 474-479

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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.

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© by the PHARMACEUTICAL SOCIETY OF JAPAN
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