In vitro metabolism of the analgesic bicifadine in the mouse, rat, monkey, and human

Drug Metab Dispos. 2007 Dec;35(12):2232-41. doi: 10.1124/dmd.107.016055. Epub 2007 Sep 19.

Abstract

The in vitro metabolism of [(14)C]bicifadine by hepatic microsomes and hepatocytes from mouse, rat, monkey, and human was compared using radiometric high-performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Two main metabolic pathways were identified in all four species. One pathway was an NADPH-dependent pathway in which the methyl group was oxidized to form a hydroxymethyl metabolite (M2). Its formation was inhibited in human microsomes only by quinidine, a CYP2D6 inhibitor. In incubations with individual cDNA-expressed human cytochromes P450, M2 was formed only by CYP2D6 and CYP1A2, with CYP2D6 activity 6-fold greater than that of CYP1A2. M2 was oxidized further to the carboxylic acid metabolite (M3) by hepatocytes from all four species. The second major metabolic pathway was an NADPH-independent oxidation at the C2 position of the pyrrolidine ring, forming a lactam metabolite (M12). This reaction was almost completely inhibited in human hepatic microsomes and mitochondria by the monoamine oxidase (MAO)-B-specific inhibitor selegiline. Clorgyline, a specific inhibitor of MAO-A, was less effective in inhibiting M12 formation. Other metabolic pathways of variable significance among the four species included the formation of carbamoyl-O-glucuronide, hydroxymethyl lactam, and carboxyl lactam. Overall, the data indicate that the primary enzymes responsible for the primary metabolism of bicifadine in humans are MAO-B and CYP2D6.

Publication types

  • Comparative Study

MeSH terms

  • Analgesics / metabolism*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism*
  • Carbon Radioisotopes
  • Carboxylic Acids / metabolism
  • Chromatography, High Pressure Liquid
  • Clorgyline / pharmacology
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors / pharmacology
  • Female
  • Glucuronides / metabolism
  • Hepatocytes / enzymology
  • Humans
  • Hydroxylation
  • In Vitro Techniques
  • Lactams / metabolism
  • Liver / cytology
  • Liver / drug effects
  • Liver / enzymology*
  • Macaca fascicularis
  • Male
  • Mice
  • Microsomes, Liver / enzymology
  • Middle Aged
  • Mitochondria, Liver / enzymology
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / pharmacology
  • NADP / metabolism
  • Oxidation-Reduction
  • Quinidine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / metabolism
  • Selegiline / pharmacology
  • Species Specificity
  • Tandem Mass Spectrometry

Substances

  • Analgesics
  • Bridged Bicyclo Compounds, Heterocyclic
  • Carbon Radioisotopes
  • Carboxylic Acids
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors
  • Glucuronides
  • Lactams
  • Monoamine Oxidase Inhibitors
  • Recombinant Proteins
  • Selegiline
  • NADP
  • bicifadine
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2D6
  • Monoamine Oxidase
  • Quinidine
  • Clorgyline