METABOLISM OF PHOLCODINE IN MAN

Abstract

This paper describes studies on the metabolism of the antitussive 3-O-(-2''-morpholinoethyl)-morphine (pholcodine, Tussokon) in man. The metabolites were identified after cleavage of conjugates, extraction and derivatization by acetylation in human urine using gas chromatography-mass spectrometry. The following seven metabolites could be identified besides the unchanged pholocodine (P): NorP, desmorpholino-hydroxy-P, nor-desmorpholino-hydroxy-P, hydroxy-P, oxo-P, nor-oxo-P and morphine in traces. Therefore, the following four partly overlapping phase I metabolic pathways can be postulated: N-demethylation, N-desalkylation at the morpholino ring followed by reduction of the resulting aldehyde to the desmorpholino-hydroxy metabolite, oxidation of the morpholino ring to the hydroxy and oxo metabolite, and O-desalkylation to morphine. With the exception of morphine, pholcodine and its phase I metabolites were not converted to enzyme hydrolysable conjugates. Pholcodine itself could be detected in urine 5-7 weeks after ingestion, the desmorpholino-hydroxy metabolite 1-2 weeks and the other metabolites only in the first few hours. It can be concluded that the low metabolism of the rather lipophilic pholcodine is the reason for the very slow elimination.