METABOLISM OF A NEW CARDIOTONIC AGENT, (-)-ALPHA-(3,4-DIMETHOXYPHENETHYLAMINOMETHYL)-4-HYDROXYBENZYL ALCOHOL (TA-064), IN MAN - O-DEMETHYLATION AND RING HYDROXYLATION

Abstract

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 5 volunteers was 14.4 ng/ml. About 30-40% of the dose was excreted as free and conjugated TA-064 and conjugates of 5 metabolites in the human 24-h urine. The 5 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. The metabolic reactions involved are demethylation at either 1 of the 2 adjacent methoxy functions and hydroxylation at the ortho position to the phenolic hydroxy group followed by methylation of either 1 of the 2 vicinal hydroxy groups. The ratio of 4''- and 3''-demethyl-TA-064, which of the dimethoxy functions was the 1 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 1 of catecholic dihydroxy function, was 6:1.