Metabolic Fate of MC903 (1): Absorption, Distribution, Metabolism, Excretion, Transfer into Fetus and Milk of MC903 after Single Subcutaneous Administration in Rats

The absorption, distribution, metabolism, excretion, transfer into the fetus and milk of MC903 were investigated in rats after a single subcutaneous administration (2 μg/kg). 1. The level of radioactivity in the plasma reached a Cmax at 1 hr, the reafter decreased with a t1/2 (2-8 hr) of 2.1 hr and a t1/2 (24-120 hr) of 2.4 days in male rats. Similar results were obtained in female rats. The linearity was observed in the dose range of 0.4 ?? 10 μg/kg. 2. The maximal levels of radioactivity, in examine d tissues of male rats, were reached at 1 hr. The elimination of radioactivity from tissues was slow. 3. The binding ability of MC903 to plasma protein was high in male rats. It was reversible in the in vitro conditions, but time-dependent increase of irreversible binding was observed in vivo. 4. Total recovery of radioactivity in male rats within 168 hr was 12.2, 68.5 and 1.3% in urine, feces and in expired air, respectively. Similar results were obtained in female rats. The entero-hepatic circulation of radioactivity was also observed. 5. The concentration of the unchanged drug in plasma was 961 μg/ml at 15 min after administration, and thereafter decreased rapidly. MC1080, RP7 and EB1057 were main metabolites of MC903. Trace of the unchanged drug was detected in pooled urine, feces and bile collected for 24 hr. Main metabolic species such as RU1 in urine, RF19 and MC1235 in feces, RB11, RB5 and RB7 in bile, were found. MC1080 and RU were detected in the liver and MC1080 and RK6 were found in the kidney. 6. The radioactivity in total fetuses or in the examined fetal tissues was lower than that found in maternal blood. 7. The profile of radioactivity in milk from lactating rats was similar to that in maternal plasma.