Metabolic Fate of a New Dihydropyridine Calcium Antagonist, NB-818. (III). Absorption, Distribution,Metabolism and Excretion after Repeated Administration in Rats and Dogs.

Abstract

The absorption, distribution, metabolism and excretion of isopropyl methyl (±)-2-carbamoyloxymethyl-4-(2, 3-dichlorophenyl)-1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate (NB-818) were studied after repeated oral doses to rats (10mg/kg/day, 3weeks) and dogs (5mg/ kg/day, 54 weeks).1. The levels of radioactivity in the plasma at 24hr after each administration of 14C-NB-818 to male rats increased by repeated dosing until the 18th dosing. The average level after the last dosing was 1.8 times higher than that after the first dosing. The plasma levels of radioactivity after the last dosing reached the peak of 6.4μg equiv./ml at 3.5hr, and declined with a half-life of 11.8hr.2. At 24hr after the last of 21 daily oral treatments, the concentrations of radioactivity in most of the male rat tissues were 2-14 times higher than those after the single dose. However, the tissue distribution patterns in both cases were similar. Disappearance of radioactivity from the tissues after 21 days of dosing was slower than after single dosing, but radioactivity did not remain in the tissues for a long period.3. The excretion of radioactivity in urine and feces was nearly constant during the period of repeated administration in male rats. Within 168hr after the last dosing, urinary and fecal excretion amounted to 7.6% and 82.3% of administered dose, respectively.4. In the case of the repeated oral dosing of NB-818 for 54 weeks to male and female dogs, plasma levels of unchanged drug showed little change.5. The profile of the urinary metabolites showed no marked change during the period of repeated administration in male and female dogs.