Stereoselective metabolism of famprofazone in humans: N-dealkylation and beta- and p-hydroxylation.

H S Shin

Index: Chirality 9(1) , 52-8, (1997)

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Abstract

Following administration of famprofazone to humans, the stereoselective metabolism from the drug to its known metabolites (+,-)-ephedrine, (+,-)-pseudoephedrine, (+,-)-norephedrine, (+,-)-norpseudoephedrine, (+,-)-p-hyroxyamphetamine, (+,-)-p-hydroxymethamphetamine, and (+,-)-p-hydroxynorephedrine was studied. The enantiomers of the metabolites were derivatized with alpha-methoxy-alpha -(trifluoromethyl)-phenylacetyl chloride (MPTA.Cl) as the chiral derivatizing agent for amino groups and N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) or N-methyl-N-triethylsilyl trifluoroacetamide (MTESTFA) as protecting agents of the hydroxyl groups. The diastereomeric derivatives were well separated by capillary gas-liquid chromatography and determined by mass spectrometry with selected-ion monitoring (SIM). (-)-Methamphetamine, (-)-amphetamine, (-)-p-hydroxyamphetamine, and (-)-p-hydroxymethamphetamine were exerted in greater amounts than their enantiomers after administration of racemic famprofazone; and (-)-ephedrine, (-)-pseudoephedrine, (-)-norephedrine, and (-)-norpseudoephedrine were found in higher concentration than their enantiomers. Famprofazone was metabolized by product and substrate stereoselective N-dealkylation, beta-hydroxylation, and p-hydroxylation, metabolites of which may be predominantly responsible for the side effects of famprofazone.