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The metabolism of [14C] verapamil was studied in fats and dogs at dose levels similar to those employed during human therapy. Verapamil is well absorbed, rapidly metabolized, and eliminated largely in feces of both species. Little tissue accumulation occurs in rats. The 7 major drug-related substances in the urine and feces of dogs were isolated and identified by mass spectrometry as various Oand N-dealkaylated metabolites of drug. Major urinary and plasma metabolites represent N-dealkylated products of verapamil which retain the a-isopropylphenylacetonitrile portion of the molecule. A. gas chromatographic assay was developed which measures 2 of these metabolites, l-isopropyl-l-V-methylpropylamino-(3,4-dimethoxyphenyl)acetonitrile and 1-isopropyl-1propylamino-(3,4-dimethoxyphenyl)acetonitrile, in plasma. Major fecal Metabolites reflect the importance of hepatic Oand N-demethylation processes. It was concluded from comparative studies that pathways of metabolism of verapamil are similar in rats, although different rates of metabolism are indicated. The major metabolite in the blood stream of dogs was also found in the plasma of several angina patients receiving verapamil.

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