Metabolic Fate or Clonidine. (II): Absorption, Distribution and Excretion in Rats and Dogs after Dermal Application of Clonidine Tape, M-5041T.

Abstract

After application of a transdermal delivery system for 14C-clonidine, 14C-M-5041T, to male rats and a dog for 24 hr, the absorption, distribution and excretion of radioactivity were investigated. 1. In the male rats, applied with a dose of 2.5, 5, 10 and 20 mg/kg, the radioactivity levels in plasma reached respective maxima at 6 or 8 hr and then declined in a biphasic manner. Within 168 hr, 4.3 to 11.1% and 1.2 to 4.3% of the dose were excreted in the urine and feces, respectively. The percutaneous absorption ratio was estimated to be about 11%. Most tissues showed higher radioactivity levels than that in the plasma, especially high levels were observed in the mandibular gland and kidney at a dose of 5 mg/kg. After removal of the system, the elimination was rapid except the aorta, thyroid gland and liver. High radioactivity was also found in the gastro-intestinal contents, some exocrine glands and nasal cavity as evidenced by the whole body autoradiograms. 2. The microautoradiograms taken at the application site of a male rat revealed tha t the radioactivity was found in the stratum corneum and then distributed uniformly in the dermis. At 120 hr (96 hr after removal), the radioactivity remained in the stratum corneum. 3. When the stratum corneum of skin was removed in a male rat at a dose of 1 mg/kg, the absorption ratio calculated from AUC was about 60%. 4. In the male dog, applied with a dose of 5 mg/kg, 4.3% of the dose was excreted in the urine and feces within 480 hr. The radioactivity level in plasma reached a maximum at 8 hr after application and then declined with a biphasic fashion.