Metabolism of Alkenebenzene Derivatives in the Rat I.p-Methoxyallylbenzene (Estragole) andp-Methoxypropenylbenzene (Anethole)

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Abstract
1. The metabolism of p-methoxyallylbenzene (estragole) and p-methoxy-propenylbenzene (anethole) in the rat has been investigated. The metabolites were identified and quantitatively determined mainly by g.l.c. and by combined g.l.c.-mass spectrometry. 2. The major metabolic reactions of p-methoxyallylbenzene were found to be O-demethylation to p-hydroxyallylbenzene and oxidation of the allylic side chain to p-hydroxy-3-(p-methoxyphenyl)propionic acid or to p-methoxybenzoic acid (anisic acid) which was largely excreted as p-methoxyhippuric acid. The former oxidative pathway involved epoxidation of the double bond and subsequent hydration to the diol whereas the latter pathway involved migration of the double bond and the formation of cinnamoyl intermediates. Other reactions gave rise to 1-(p-methoxyphenyl)allyl alcohol and to p-methoxyphenylacetic acid and its glycine conjugate. A total of at least 60–65% but as much as 90% dose was accounted for. 3. A major metabolic reaction of p-methoxypropenylbenzene was found to be O-demethylation which gave rise to p-hydroxypropenylbenzene and p-hydroxycinnamic acid. Metabolism via cinnamoyl derivatives was more extensive with the propenyl than with the allyl compound and further metabolism by β-oxidation occurred. This resulted in the formation of anisic acid which was excreted largely as its glycine conjugate, the major urinary metabolite. Epoxidation of the side chain appeared to be a minor metabolic reaction with the propenyl derivative. Essentially quantitative recovery of the dose was achieved. 4. The biliary metabolites of p-methoxyallylbenzene and p-methoxypropenylbenzene were identified and most of the urinary metabolites were also found in the bile. Further information on and confirmation of the routes of metabolism were obtained by identifying the metabolites of key intermediates including p-methoxycinnamic acid and the epoxides of estragole and anethole.