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Drug Res (Stuttg) 2015; 65(09): 500-504
DOI: 10.1055/s-0034-1390457
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Studies on the Biotransformation of Veratric Acid, a Human Metabolite of Mebeverine, by Using the Incubated Hen’s Egg

L. Kiep
1   Private Laboratory, Brunow, Germany
,
M. Göhl
2   Department of Organic Chemistry, Faculty of Biology, Chemistry and Earth Sciences, University of Bayreuth, Germany
,
J. Schmidt
3   Leibniz Institute of Plant Biochemistry, Halle, Germany
,
K. Seifert
2   Department of Organic Chemistry, Faculty of Biology, Chemistry and Earth Sciences, University of Bayreuth, Germany
› Author Affiliations
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Publication History

received 14 July 2014

accepted 08 September 2014

Publication Date:
13 October 2014 (online)

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Abstract

Metabolism studies with selected test substances have shown that a model on the basis of the incubated hen’s egg is suitable as a supplement to animal experimentation. Because of its 3,4-dimethoxyphenyl structure veratric acid (3,4-dimethoxybenzoic acid), a known human metabolite of mebeverine, was chosen as model substance for the present investigations and the parent compound as well as 4-hydroxy-3-methoxybenzoic acid were identified as main metabolites. The absence of 3-hydroxy-4-methoxybenzoic acid lets conclude that the O-demethylation takes place exclusively at the p-methoxyl function. In addition, 3,3’,4,4’-tetramethoxy-l-ornithuric acid (2,5-bis-(3,4-dimethoxybenzoylamino)pentanoic acid) and its O-desmethyl derivative could be characterized as further metabolites. So far an amino acid conjugate has not been described after veratric acid administration in a vertebrate. There were no indications for the appearance of 3,4-dihydroxybenzoic acid in the veratric acid metabolism. This was confirmed by corresponding studies having the isomeric guaiacol acids as precursor. Furthermore, it could be proved that in ovo the O-methylation of 3,4-dihydroxybenzoic acid occurs regioselective at the m-hydroxyl group. The results which broaden the knowledge on the metabolic fate of veratric acid are discussed in comparison with those in mammals. The metabolites were identified by GC-MS, ESI-HRMS and LC/ESI-MS/MS. The structure of the synthesized reference substance was confirmed by MS, 1H and 13C NMR spectral data.

Key words

complementary method to animal testing - 3,4-dimethoxyphenyl moiety - guaiacol acids - O-demethylation - O-methylation - amino acid conjugation

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