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In vitro confirmation of selegiline N-oxidation by flavin-containing monooxygenase in rat microsome using LC-ESI MS.

Abstract
In order to investigate the conversion of selegiline (SG), a drug used in the treatment of Parkinson's disease, to selegiline N-oxide (SGO) as a major metabolic pathway for SG, rat liver microsomal incubations were carried out in vitro in the presence of NADPH. SG was transformed into SGO in vitro as described in our previous human in vivo experiment. In the kinetic studies, the Vmax/Km value of the N-oxidation at pH 8 was found to be approximately four times greater than that at pH 7.4. The N-oxidation was also found to be inhibited by methimazole, an inhibitor of the flavin-containing monooxigenase (FMO) rather than by SKF 525A, an inhibitor of cytochrome P450s, and stimulated approximately two times by n-octylamine, an stimulator of FMO. Moreover, the N-oxidation activity remained almost unchanged in the presence of NADPH even after heating at 50 degrees C for a few minutes. The present data demonstrate that the N-oxidation of SG to SGO is principally mediated by FMO.
AuthorsHiroe Tsutsumi, Munehiro Katagi, Mayumi Nishikawa, Hitoshi Tsuchihashi, Fumiyo Kasuya, Kazuo Igarashi
JournalBiological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 27 Issue 10 Pg. 1572-5 (Oct 2004) ISSN: 0918-6158 [Print] Japan
PMID15467197 (Publication Type: Journal Article)
Chemical References
  • Amines
  • Antiparkinson Agents
  • Enzyme Inhibitors
  • selegiline-N-oxide
  • Selegiline
  • NADP
  • Methimazole
  • Proadifen
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • octylamine
Topics
  • Amines (pharmacology)
  • Animals
  • Antiparkinson Agents (metabolism, pharmacokinetics)
  • Chromatography, Liquid
  • Enzyme Inhibitors (pharmacology)
  • Heating
  • Hydrogen-Ion Concentration
  • In Vitro Techniques
  • Methimazole (pharmacology)
  • Microsomes, Liver (enzymology, metabolism)
  • NADP (metabolism)
  • Oxidation-Reduction
  • Oxygenases (metabolism)
  • Proadifen (pharmacology)
  • Rats
  • Selegiline (analogs & derivatives, metabolism, pharmacokinetics)
  • Spectrometry, Mass, Electrospray Ionization

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