Interactions of monoamine oxidase inhibitors, N-acetylenic analogues of tryptamine, with rat liver microsomal cytochrome P450.
Interactions between some novel and potent monoamine oxidase inhibitors (MAOIs), acetylenic analogues of tryptamine, and rat liver microsomal cytochrome P450 (P450) as evidenced by visible spectra analysis were analysed. Compounds with a secondary aliphatic amine moiety throughout induced type II difference spectra and exhibited the highest affinity for P450, whereas tertiary amines induced type I spectral changes and showed diminished affinity. P450 dependent aniline hydroxylase activity was inhibited by all compounds in an irreversible time-dependent manner. Only tertiary aliphatic amines constituted the substrate for P450-dependent N-demethylase activity, with comparable kinetic parameters. The N-demethylated metabolites were identified by thin-layer chromatography and mass-spectrometric analyses. These findings describe the role of P450-dependent microsomal mono-oxygenase systems in the metabolism of some MAOI acetylenic tryptamine derivatives and the possible hepatic contribution to adverse interactions between MAOIs, endobiotics and sympathomimetic compounds.
Valoti
M
M
Centro di Ricerca sul Metabolismo dei Farmaci Psicotropi, Istituto di Scienze Farmacologiche, Università di Siena, Italy.
Costanzo
M
M
Sgaragli
G P
GP
Perez
V
V
Fernandez-Alvarez
E
E
Unzeta
M
M
D000114:Acetylene / Q000378:metabolism*; D000815:Aniline Hydroxylase / Q000037:antagonists & inhibitors; D000818:Animals; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology*; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013057:Spectrum Analysis; D014363:Tryptamines / Q000378:metabolism*
D008996:Monoamine Oxidase Inhibitors; D014363:Tryptamines; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D000114:Acetylene