On the metabolism of the amphetamine-derived antispasmodic drug mebeverine: Gas chromatography-mass spectrometry studies on rat liver microsomes and on human urine

We describe gas chromatography-mass spectrometry studies of the metabolism of the antispasmodic drug mebeverine [Duspatal, (MB)]. MB is the veratric acid (VA) ester of 4-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}butan-1-ol (MB-OH), which is an N-substituted ethylamphetamine derivative. The metabolites were first identified in rat liver microsome incubates and then detected in urine samples of volunteers through the use of electron impact and positive chemical ionization gas chromatography-mass spectrometry. Urinary conjugates were enzymatically cleaved before analysis. The following phase I metabolites of MB could be identified: VA, O-demethyl VA (vanillic and/or isovanillic acid), O-bisdemethyl VA (protocatechuic acid), MB-OH, hydroxy MB-OH, O-demethyl MB-OH, O-demethyl-hydroxy MB-OH, N-desethyl MB-OH, N-desethyl-O-demethyl MB-OH, N-de(hydroxybutyl) MB-OH (methoxy-ethylamphetamine), N- de(hydroxybutyl)-O-demethyl MB-OH (hydroxy-ethylamphetamine), and N-bisdealkyl MB-OH (p-methoxyamphetamine, known as the designer drug PMA). The following, partly overlapping metabolic pathways of MB could be postulated: ester hydrolysis, O-demethylation, ring hydroxylation, N- deethylation, and N-de(hydroxybutylation). The latter pathway led to ethylamphetamine derivatives and bisdealkylation led to PMA, which are substances of forensic interest. The metabolites containing alcoholic or phenolic hydroxy groups were partly excreted into urine as conjugates.