In Vitro Confirmation of Selegiline N-Oxidation by Flavin-Containing Monooxygenase in Rat Microsome Using LC-ESI MS(Toxicology)

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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 V_<max>/K_m 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℃ for a few minutes. The present data demonstrate that the N-oxidation of SG to SGO is principally mediated by FMO.
2004-10-01