Metabolic Degradation of Clonidine

Abstract

¹⁴C-clonidine was administered orally to dogs (Beagles) for 5 days. 6 radioactive substances eliminated with the urine could be isolated. They were identified by mass spectrometry and comparison with synthetic material. The presence of unchanged clonidine, p-hydroxy-clonidine, and dichlorophenylguanidine was confirmed and 3 new metabolites were detected: 1-(2,6-dichloro-4-hydroxyphenyl)guanidine; 2- [(2,6-dichlorophenyl)imino]imidazolidine-4-one, and 2- [(2,6-dichloro-4-hydroxyphenyl)-imino]imidazolidine-4-one. The cleavage of the imidazolidine ring and the hydroxylation of the phenyl ring are the two principal routes of metabolism. In an additional experiment, the metabolic patterns in the urine of man, rat, and dog were compared after a single oral dose of labelled clonidine. It could be demonstrated that the 6 identified compounds were eliminated by all 3 species, the relative amounts, however, were different. Man eliminated clonidine mainly in the unchanged form. In the urine of the rat a considerable amount of the parent drug could be detected but the metabolites predominated. Of the 3 species investigated the dog metabolized clonidine most readily with dichlorophenylguanidine as its main metabolite.