[Cross-reactivities of active metabolites in the radioreceptor assay of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)- 1H-benzimidazole difumarate (KG-2413)]

Yakugaku Zasshi. 1989 Jul;109(7):474-9. doi: 10.1248/yakushi1947.109.7_474.
[Article in Japanese]


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.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • English Abstract

MeSH terms

  • Animals
  • Benzimidazoles / blood
  • Benzimidazoles / pharmacokinetics*
  • Chromatography, Gas
  • Guinea Pigs
  • Histamine H1 Antagonists / blood
  • Histamine H1 Antagonists / pharmacokinetics*
  • Male
  • Radioligand Assay*


  • Benzimidazoles
  • Histamine H1 Antagonists
  • emedastine