Metabolism of ebrotidine. A review

A hypothetical metabolic pathway for ebrotidine (N-[(E)-[[(2-[[[2-[(diaminomethylene]amino]-4-thiazolyl] methyl]thio]ethyl]amino]methylene-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) has been proposed on the basis of previous data on the metabolism of other H2-receptor antagonists as well as on in vitro degradation assays of ebrotidine. Its potential metabolites have been synthesized and characterized, and their presence in human urine has been investigated by high-performance liquid chromatography (HPLC). Analytical-scale HPLC allowed the identification of metabolites by means of their retention time and UV spectrum, while semipreparative-scale HPLC allowed their identification through FT-IR and 1H-NMR. Mass spectrometry using atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI) for HPLC-MS coupling allowed the identification of all metabolites in human urine. The quantitative determination of ebrotidine and its derivatives has been performed according to a newly designed method which consisted of a liquid-liquid extraction in a basic medium followed by reversed-phase HPLC with ion-pair formation. This method was sensitive, precise and no chromatographic interferences with other drugs which might be administered in combination with ebrotidine were observed. In order to elucidate the excretion of ebrotidine, the analytical method was applied to the analysis of the urine collected from 2 healthy volunteers 96 h after receiving 400 mg of ebrotidine.