Metabolic fate of a new dihydropyridine calcium antagonist, CD-349, in rat and dog

Abstract

1. The metabolic fate of ¹⁴C-CD-349, a new calcium antagonist, was studied in rat and dog.

2. After oral administration of ¹⁴C-labelled drug in both species, the plasma levels of radioactivity reached maxima at 1–2 h and declined with elimination half-lives of 6–7 h. In both species, 71–85% of radioactivity was excreted in faeces and 17–27% in urine in 120h. Biliary excretion in rat after oral doses amounted to 33%.

3. The low ratio of unchanged drug to total radioactivity in plasma suggested that CD-349 underwent rapid metabolism in both species.

4. Twenty-two metabolites were isolated and identified from dog urine and an incubation mixture with 9000 g rat liver supernatant. Principal routes of biotransformation of CD-349 were similar in both species, and involved: (1) oxidation of the dihydropyridine ring to the corresponding pyridine ring; (2) denitration of the nitrate ester; (3) hydrolysis of the carboxy ester to the carboxylic acid; and/or (4) oxidation of the side chain, although quantitative interspecies differences were observed.