Metabolism of the Antihypertensive Agent 1,4-Dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-3,5-pyridinedicarboxylic Acid Diethyl Ester

The absorption, distribution, metabolism, and excretion of 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-3,5-pyridinedicarboxylic acid diethyl ester, an antihypertensive drug, was studied in rat, dog, and squirrel monkey. The drug, labeled with 14C, was found to undergo aromatization, hydrolysis of its ester groups, and oxidation of a ring methyl and an ethyl group. No dihydropyridyl metabolites or the hypothetical aromatized parent compound were found. The metabolites identified were: 2,6 - dimethyl - 4 - (2 - trifluoromethylphenyl) - 3,5 - pyridinedicar-boxylic acid, its monoethyl and mono-2-hydroxyethyl esters, and 2-hydroxymethyl - 6 - methyl - 4 - (2 - trifluoromethylphenyl) - 3,5-pyridinedicarboxylic acid lactone. The form in which the drug was administered was found to have a profound effect on its absorption. The crystalline powder administered to dogs in gelatin capsules was poorly absorbed; solubilization with polyethylene glycol 200 resulted in a fivefold increase in absorption.