Abstract
The absorption, distribution, metabolism, excretion and the effect of MC903 on hepatic drug metabolizing enzymes were investigated in male rats after multiple dermal application in 5 μg/100 mg ointment/body/day using an occlusive dressing technique or subcutaneous administration at the dose of 2 μg/kg/day.
1. After multiple dermal application, the radioactivity level in the plasma 24 hr after daily dosing reached a plateau level after the 5th dosing. The Cmax after the 7th dosing was 8.3 times higher as compared with those after a single dosing, but the elimination of radioactivity was slow. Increase in total recovery of radioactivity in urine, feces and expired air was dependent on the number of dosing. Total recovery of radiaoctivity within 168 hr after the 7th dosing was 5.4, 30.7 and 1.9% in urine, feces and in expired air, respectively.
2. After multiple subcutaneous administration, the radioactivity level in the plasma 24 hr after daily dosing reached a plateau level after the 9th dosing. The radioactivity level in the plasma after the 21st dosing was higher than that after a single dosing. The excretion rates of radioactivity in urine, feces and expired air reached a plateau level after the 11th dosing. Total recovery of radioactivity within 168 hr after the 21st dosing was 16.6, 72.0 and 5.6%in urine, feces and in expired air, respectively.
3. After multiple subcutaneous administration, the radioactivity levels in examined tissues 24 hr after daily dosing gradually increased in parallel to number of dosings. The radioactivity levels in tissues after the 21st dosing decreased slowly as compared with those after a single dosing.
4. After multiple subcutaneous administration, the concentration of the unchanged drug in plasma was 605 pg/ml at 15 min after the 21st dosing, and thereafter rapidly decreased. MC1080 and RP7 were found as main metabolites. The ratio of the unchanged drug to its metabolites in pooled urine and feces collected for 24 hr after the 21st dosing was similar to that after a single dosing. Trace of the unchanged drug was found in the liver at 1 hr after the 21st dosing, and MC1080 and RU were found as main metabolites. The unchanged drug and main metabolites, MC1080 and RK6, were found in the kidney.
5. After multiple subcutaneous administration, the effect on hepatic drug metabolizing enzymes was slight and reversible.
