Metabolism of a new cardiotonic agent, (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol (TA-064), in man. O-demethylation and ring hydroxylation.

A method is described for the determination of plasma concentration of (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl alcohol (TA-064), a new, selectively inotropic cardiotonic agent, based on selected ion monitoring gas chromatography-mass spectrometry. The plasma TA-064 concentration rose rapidly and reached a peak within 60 min after oral administration. The mean peak value of five volunteers was 14.4 ng/ml. About 30-40% of the dose was excreted as free and conjugated TA-064 and conjugates of five metabolites in the human 24-hr urine. The five urinary metabolites were characterized by mass spectrometry after gas- or high performance liquid chromatographic separation: they were 4'-demethyl-, 3-methoxy-, and 4'-demethyl-3-methoxy-TA-064 as the major and 3'-demethyl- and 3-hydroxy-4-methoxy-TA-064 as the minor metabolites. Therefore, the metabolic reactions involved are demethylation at either one of the two adjacent methoxy functions and hydroxylation at the ortho position to the phenolic hydroxy group followed by methylation of either one of the two vicinal hydroxy groups. The ratio of 4'- and 3'-demethyl-TA-064, which of the dimethoxy functions was the one demethylated, was 17:1, and that of 3-methoxy-4-hydroxy- and 3-hydroxy-4-methoxy-TA-064, the phenolic moiety which was vicinally hydroxylated followed by methylation of one of catecholic dihydroxy function, was 6:1.