Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug

Xenobiotica. 1987 May;17(5):559-73. doi: 10.3109/00498258709043963.

Abstract

The metabolism of the anti-hypertensive drug, mopidralazine, N-(2',5'-dimethyl-1H-pyrrol-1-yl)-6-(4"-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2'(5')-13CH3]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine. The previously proposed mesonic structure of the major metabolite I, i.e., 5'-hydroxy-3',6'-dimethyl-1'-[6-(4"-morpholinyl)-3-pyridazinyl]pyrida zinium hydroxide inner salt, was confirmed by chemical synthesis, X-ray diffraction analysis and 1H n.m.r. of the [3',6'-13CH3]-labelled metabolite I. Metabolite II, 3-methyl-6-(4-morpholinyl)-triazolo [4,3-6 b]pyridazine and metabolite VII, 3-methyl-7-(4-morpholinyl)-3H-pyridazino[1,6-c]pyridazine, were shown to retain the 13CH3 labelling of mopidralazine, whereas metabolite X, 3-acetyl-hydrazino-6-(4-morpholinyl)-pyridazine, loses the labelling, indicating that their formation involves two different pathways. It is hypothesized that the oxidation of the pyrrole leads to ring opening followed by a chemical rearrangement giving rise directly to metabolites II and VII or, with the intermediacy of the pharmacologically active 3-hydrazino-6-(4-morpholinyl) derivative and an enzymic acetylation or conjugation with pyruvic acid, to metabolites X, II and VII.

MeSH terms

  • Animals
  • Antihypertensive Agents / metabolism*
  • Antihypertensive Agents / urine
  • Biotransformation
  • Magnetic Resonance Spectroscopy
  • Male
  • Mass Spectrometry
  • Oxidation-Reduction
  • Pyridazines / metabolism*
  • Pyridazines / urine
  • Pyrroles / metabolism*
  • Pyrroles / urine
  • Rats
  • Rats, Inbred Strains
  • X-Ray Diffraction

Substances

  • Antihypertensive Agents
  • Pyridazines
  • Pyrroles
  • mopidralazine