Metabolic studies of aminopyrine in rat and man by using stable isotope tracer techniques.

Abstract

The metabolites of aminopyrine (AM) were analyzed by using stable isotope tracer techniques. After the oral administration of an equimolar mixture of AM and AM-2-CD3 [4-dimethylamino-3-methyl-2-trideuteromethyl-1-phenyl-3-pyrazolin-5-one] (mixture 1), or an equimolar mixture of AM-3-CH2OH [4-dimethylamino-3-hydroxy methyl-2-methyl-1-phenyl-3-pyrazolin-5-one] and AM-3-CD2OH [4-dimethylamino-3-hydroxy dideuteromethyl-1-phenyl-3-pyrazolin-5-one] (mixture 2) or either AM-3-CD3 [4-dimethylamino-3-trideuteromethyl-2-methyl-1-phenyl-2-pyrazolin-5-one] or AM-4-N(CD3)2 [4-di(trideuteromethylamino)-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one] to rats, the urinary metabolites were extracted with chloroform at pH 7.0, and the extracts were subjected to gas chromatography-mass spectrometry (GC-MS) after trimethylsilylation. Characteristic doublet peaks in the mass spectra indicated the presence of a metabolite originating from mixture 1 or 2 mentioned above. The new metabolites detected by GC-MS were identified as 3-hydroxymethyl-4-monomethylaminoantipyrine (MAA-3-CH2OH) and 3-hydroxymethyl-4-aminoantipyrine (AA-3-CH2OH) from the shifts of the mass numbers of the molecular ions after the administration of AM-3-CD3 and AM-4-N(CD3)2. Two other metabolites were newly detected after the administration of mixture 2 (AM-3-CH2OH is an intermediary metabolite of AM) to rats. They were identified as 3-hydroxymethyl-4-acetylmonomethyl aminoantipyrine (AcMAA-3-CH2OH) and 3-hydroxymethyl-4-acetylaminoantipyrine (AcAA-3-CH2OH). MAA-3-CH2OH was detected in human urine after the oral administration of AM.