No abstract

Summary: The plasma protein binding of 14C-clonidine in vitro and in vivo and its transfer into the fetus and milk in rats were investigated.1. The binding ratios of radioactivity in vitro to male rat, dog, monkey and human plasma proteins did not change with drug concentration in any species and no marked species difference was observed, however, in vivo binding to male rat, dog and monkey plasma proteins tended to increase with the elapse of time.2. After subcutaneous administration to pregnant rats at a dose of 1 mg/kg, the radioactivity levels in the fetal kidney and liver were higher than that in the maternal plasma. The radioactivity was rapidly elimi nated from the fetal tissues as that from the maternal plasma. On the whole body autoradiograms, compara ble radioactivity was found in the fetus with the maternal plasma.3. The radioactivity level in the milk reached a maximum at 30 min after subcutaneous administration at a dose of 1 mg/kg, being 5.5 times higher than that in the plasma, but was comparable with that in the plasma after 8 hr and decreased to undetectable level at 72 hr after administration.

Summary: The metabolism of clonidine in rats, dogs and monkeys was investigated after subcutaneous ad ministration 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 af ter 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 cleavage 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.

Summary: After repeated subcutaneous administration of 14C-clonidine to male rats once a day for 21 days at a dose of 1 mg/kg/day, the absorption, distribution and excretion of radioactivity were investigated .1. No marked variation was observed in the radioactivity level of the plasma at every 24 hr after daily ad ministration. After the final dosing, the elimination of radioactivity from the plasma after 24 hr was slower than that after single dosing.2. The radioactivity levels in most tissues at 24 hr after daily administration achieved nearly a steady state by the 21st dosing, but the level in aorta increased cumulatively and the value was 10 times higher than that after the first dosing. After the final dosing, the elimination of radioactivity from the tissues after 24 hr was slower than that after single dosing. On the whole body autoradiograms, high radioactivity was also found in the gastro-intestinal content, some exocrine glands and nasal cavity.3. The total excretion of radioactivity in the urine and feces during each 24 hr after daily dosing was almost constant after the 2nd dosing and 71.6 and 26.4% of the cumulative dose were excreted in the urine and feces, respectively, within 168 hr after the final dosing.