Metabolic Fate of MC903 (4): Absorption, Metabolism and Excretion a fter Dermal Application and Subcutaneous Administration in Dogs

Abstract

The absorption, metabolism and excretion of MC903 were investigated in male dogs after dermal application (100 μg/2 g ointment/body) using an occlusive dressing technique or subcutaneous administration (2 μg/kg).
1. The radioact ivity level in the plasma reached a C_max at 24 hr after dermal application, and thereafter decreased with a t_1/2 (48-168 hr) of 5.5 days. The radioactivity level in the plasma reached a C_max at 2 hr after subcutaneous administration, and thereafter decreased with a t_1/2 (4-8 hr) of 7.5 hr and a t_1/2 (24-168 hr)of 3.5 days.
2. Total recovery of radioactivity within 168 hr after dermal application was 0.6 and 5.3% in urine and feces, respectively. Total recovery of radio activity within 168 hr after subcutaneous administration was 5.9 and 78.8% in urine and feces, respectively.
3. The binding abilities of MC903 to plasma protein of dogs (in vitro and in vivo) and human (in vitro) were high and reversible. MC903 was mainly bound to albumin.
4. The concentration of the unchanged drug in plasma was C_max of 632 μg/ml at 1 hr after subcutaneous administration and thereafter decreased with a t_1/2 of 1.7 hr up to 8 hr. MC1080 was a main metabolite of MC903. Trace of the unchanged drug was detected in pooled urine and feces collected for 48 hr. DU1 and DU2 (glucuronide of MC1235) were main metabolites found in the urine. DF4 and MC1235 were those found in feces.