Metabolic Fate of NKH477. (2). Blood Concentration, Distribution, Excretion and Effects on Drug-Metabolizing Enzyme System in Rats after Repeated Intravenous Administration.

Abstract

The blood concentration, distribution and excretion of radioactivity were investigated in male rats after daily intravenous administration of 14C-NKH477 for 21 days. The effects of NKH477 on hepatic drug metabolizing enzyme system were also investigated in male rats. 1. The radioactivity in the blood at 24 hr after daily administration rose as number of dose increased, the elimination of radioactivity from the blood after the last dosing was slower than that after a single dosing. 2. In most tissues, the radioactivity accumulated during the period of repeated administration, especially in the spleen, blood, kidney and mesenteric lymph node that rose markedly. Disappearance of radioactivity from most tissues after the last dosing was slower compared with that after a single dosing. 3. Within 168 hr after a repeated administration for 21 days, urinary and fecal excretion amounted to 7.8% and 88.9% of cumulative dose, respectively. The ratio of excretion between urine and feces was approximately the same as after a single dosing. 4. Repeated administration of NKH477 at doses of 0.3 and 1.0 mg/kg/day for 7 days had no effect on liver weight, microsomal cytochrome P-450 contents and hepatic drug-metabolizing enzyme system.