1991 Volume 6 Issue 3 Pages 331-341
The absorption, metabolism and excretion of isopropyl methyl (±)-2-carbamoyloxymethyl-4-(2, 3-dichlorophenyl)-1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate(NB-818) were investigated after single oral (1 mg/kg) or intravenous (0.1mg/kg) administration of 14C-labelled compound to male and female dogs.
1. 14C-NB-818 was absorbed rapidly and almost completely, after oral dosing to male dogs. The plasma levels of radioactivity reached the peak of 1.24μg equiv./ml at 1.7hr, and then declined biphasically with a terminal half-life of 101.8hr. After iv dosing, the terminal half life was 89.4hr. The pharmacokinetic parameters after iv or oral dosing to female dog were similar to those in male dogs. The radioactivity in the whole blood was lower than that in plasma, but the time-profile was similar to that of plasma.
2. The plasma levels of unchanged NB-818 reached the maximum at 0.5-1hr after oral dosing, with corresponding values of 259 and 201ng/ml, and then declined with half-lives of 2.9 and 2.2hr in male and female dogs, respectively. The oral bioavailability of NB-818 amounted to 65% in male dogs.
3. After oral dosing to male and female dogs, the excretion of the radioactivity in feces and urine during 168hr was 68.5% and 26.3% and 65.4% and 28.5%, respectively. The excretion of radioactivity in feces and urine after iv dosing was similar to that after oral dosing. Fecal excretion was the major excretory route in dogs. The excretion of the unchanged drug to urine was negligible. These results indicate that NB-818 is extensively metabolized.
4. The serum protein binding of NB-818 in vitro was more than 94%.
5. The main components of radioactivity in plasma consisted of the unchanged drug, M-3 and M-5. In urine and feces, M-8 was the major metabolite. The metabolite profiles in urine of male and female dogs were quantitatively similar.
6. No sex difference was observed in the metabolism and disposition of 14C-NB-818 in dogs.
7. Comparing the metabolism and disposition of NB-818 in dogs to that in rats, a remarkable species difference in the metabolism was observed.
