Metabolic Fate of Clonidine (V): Metabolism of Clonidine after Subcutaneous Administration of Clonidine to Rats, Dogs and Monkeys and Dermal Application of Clonidine Tape, M-5041T, to Rats

The metabolism of clonidine in rats, dogs and monkeys was investigated after subcutaneous administration of 14C-clonidine or after application of a transdermal delivery system containing 14C-clonidine, 14C-M-5041T. 1. In male rats after subcutaneous dosing, unchanged clonidine was mainly found in the urine, followed by the conjugate of CM-4, a hydroxylated metabolite of the phenyl ring. CM-4 was also found in the feces and bile. 2. The metabolic profile in male rats after 21 times repeated subcutaneous dosing was similar to that after single dosing. Certain metabolites were bound tightly to the constituent proteins of aorta. 3. Unchanged clonidine was mainly found in the skin at the application site of male rats after application of 14C-M-5041T. The metabolic profile was similar to that after subcutaneous dosing. 4. In male dogs after subcutaneous dosing, CM-1, a metabolite formed by cle avage of the imidazolidine ring, was mainly found, whereas the unchanged clonidine was found in minor quantities in the urine and feces. The metabolic profile in a male monkey was similar to that in dogs. 5. From the above results, main metabolic pathways of clonidine were proposed to be the hydroxylation and conjugation of the phenyl ring in rats, and the oxidation and cleavage of the imidazolidine ring in dogs and monkeys.