Metabolism of A dopamine D(4)-selective antagonist in rat, monkey, and humans: formation of A novel mercapturic acid adduct

Drug Metab Dispos. 2000 Jun;28(6):633-42.

Abstract

3-([4-(4-Chlorophenyl)piperazin-1-yl]-methyl)-1H-pyrrolo-2, 3-beta-pyridine (L-745,870) is a dopamine D(4) selective antagonist that has been studied as a potential treatment for schizophrenia, with the expectation that it would not exhibit the extrapyramidal side effects often observed with the use of classical antipsychotic agents. The metabolism of L-745,870 in vivo was investigated in the rat, rhesus monkey, and human using liquid chromatography-tandem mass spectrometry and/or NMR techniques in conjunction with radiochemical detection. In all three species, two major metabolic pathways were identified, namely N-dealkylation at the substituted piperazine moiety and the formation of a novel mercapturic acid adduct. It is proposed that the latter biotransformation process involves the formation of an electrophilic imine methide intermediate, analogous to that produced from 3-methyl indole. This report appears to represent the first example of metabolic activation of a 3-alkyl-7-azaindole nucleus.

MeSH terms

  • Acetylcysteine / metabolism
  • Acetylcysteine / urine*
  • Animals
  • Dopamine Antagonists / metabolism*
  • Dopamine Antagonists / pharmacology
  • Dopamine Antagonists / urine
  • Dopamine D2 Receptor Antagonists
  • Humans
  • Macaca mulatta
  • Male
  • Pyridines / metabolism*
  • Pyridines / pharmacology
  • Pyridines / urine
  • Pyrroles / metabolism*
  • Pyrroles / pharmacology
  • Pyrroles / urine
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D4

Substances

  • 3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine
  • DRD4 protein, human
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Drd4 protein, rat
  • Pyridines
  • Pyrroles
  • Receptors, Dopamine D2
  • Receptors, Dopamine D4
  • Acetylcysteine