Metabolism of debrisoquine sulfate. Identification of some urinary metabolites in rat and man.

A high proportion of an oral dose of 14C-debrisoquine sulfate is excreted in the urine by rat and man. The urinary radioactivity consists of a mixture of unchanged drug and polar, water-soluble metabolites which cannot be extracted into organic solvents. Treatment of methanolic extracts of the freeze dried urine with acetylacetone incorporates the amidino group of debrisoquine and these metabolites into a 4,6-dimethylpyrimidine ring, and yields derivatives which can be readily extracted from aqueous solution. Gas-liquid chromatographic-mass spectrometric studies of these extracts have shown that in both species: 1) the major metabolite is formed by 4-hydroxylation of debrisoquine; 2) a significant proportion of the dose is excreted as acidic metabolites, formed by opening the tetrahydroisoquinoline ring; 3) trace amounts of phenolic metabolites (5-, 6-, 7-, and 8-hydroxydebrisoquines) are also excreted.