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 single oral or intravenous administration of 14C-labelled compound to male and female rats.
1. After oral dosing (10mg/kg) to male and female rats, the mean peak plasma levels of radioactivity of 5.9 and 11.8μg eq./ml were observed at 1.25 and 3.5hr, respectively. Plasma half-life of radioactivity was 12.0hr in males and 4.7hr in females. After iv dosing (0.3mg/kg), plasma half-life of radioactivity was 13.5 and 6.0hr in males and females, respectively.
2. Plasma levels of unchanged NB-818 reached the maximum concentration at 0.5-1hr after oral dosing (10mg/kg), with the corresponding values of 587 and 906ng/ml, and then declined with half-lives of 2.8 and 2.2hr in male and female rats, respectively. The oral bioavailability of NB-818 in male rats amounted to 33% due to first-pass metabolism.
3. After oral dosing(10mg/kg) to male and female rats, the excretion of the radioactivity in feces and urine during 72hr was 84.0% and 8.0%, 65.1% and 27.5%, respectively. The biliary excretion within 48hr after oral dosing was 52.4% of the dose in males and 56.5% in females. The excretion of the unchanged drug to urine and bile was negligible. Radioactivity was mainly excreted into the feces via the bile and undergone enterohepatic circulation.
4. After oral dosing to male rats, radioactivity was rapidly distributed to various tissues and maintained in high concentrations in the liver and gastrointestinal tract. Radioactivity in most tissues decreased in parallel with that in plasma.
5. The serum protein binding of NB-818 in vitro was more than 98%, and that of radioactivity in vivo was more than 90% after oral dosing in male rats. The binding of radioactivity in vivo to erythrocytes was 9-19% after oral dosing.
6. In the plasma samples of both sexes after oral dosing, M-2 and M-10 were present as the main metabolites. The major metabolite found in rat urine, was M-2. The total amount of M-2 and M-10 in plasma and urine from female rats was much higher than in male rats. In the bile, M-8 was the major component of an identified metabolites. These results indicate that NB-818 was extensively metabolized.
7. A distinct sex-difference in the metabolism and disposition of 14C-NB-818 in rats was observed.
