title: Characterization of oxalic acid derivatives as new metabolites of metamizol (dipyrone) in incubated hen's egg and human.
abstract: Metamizol (dipyrone, 1), a widely used drug with effective analgesic and antispasmodic properties, shows severe side effects like agranulocytosis and anaphylactic shock reactions, the reasons of which are not known until today. After oral administration 1 is completely metabolized. All hitherto known metabolites have an intact pyrazolinone ring structure like the parent compound and are completely extractable from urine with polar organic solvents. However, only a fractional amount of the applied dosage can be recovered by this procedure. To clarify the reason of this deficit of unknown metabolites we followed the hypothesis of oxidative rupture of the heterocyclic ring during metabolism of 1. On the basis of former in vitro results we now were able to identify in quality three oxalic acid derivatives and one acetic acid phenylhydrazide as new metabolites of metamizol in the allantoic fluid (AF) of incubated hen's eggs as well as in human urine by means of GC-MS analysis and comparison with unequivocally synthesized authentic reference compounds. Whereas the oxamazide 7, the phenylhydrazide 8 and N-methyloxamic acid 9 are only present in trace concentrations and therefore cannot account for the deficit in the balance of metabolites, the oxalic acid monohydrazide 11 seems to be excreted in higher amount. But quantitative determination of this new metabolite would be required to answer the open questions concerning the biotransformation of metamizol and thereby to detect new facts about mode of action and side effects of this drug.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Wessel
authors.forename: Magdalena
authors.initials: M
authors.lastname: Matyja
authors.forename: Michael
authors.initials: M
authors.lastname: Neugebauer
authors.forename: Heiko
authors.initials: H
authors.lastname: Kiefer
authors.forename: Thomas
authors.initials: T
authors.lastname: Daldrup
authors.forename: Fuad A
authors.initials: FA
authors.lastname: Tarbah
authors.forename: Horst
authors.initials: H
authors.lastname: Weber
mesh_terms: D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001711:Biotransformation; D002645:Chickens; D004177:Dipyrone / Q000378:metabolism*; D004531:Eggs / Q000032:analysis; D004952:Esters / Q000737:chemistry / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008745:Methylation; D010070:Oxalates / Q000737:chemistry*; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D007202:Indicators and Reagents; D010070:Oxalates; D004177:Dipyrone