title: CYP-dependent metabolism of PF9601N, a new monoamine oxidase-B inhibitor, by C57BL/6 mouse and human liver microsomes.
abstract: OBJECTIVE
  The selective monoamine oxidase-B (MAO-B) inhibitor, l-deprenyl, is still used for treating Parkinson's patients, however, a disadvantage of its use lies in the formation of l-amphetamine and l-methamphetamine. Subsequently, this has promoted the design of a novel, more potent, MAO-B inhibitor PF9601N, which also has neuroprotective and antioxidant properties. The aim of this work was to investigate the effect of treatment with PF9601N on its own phase I hepatic metabolism. Kinetic parameters of PF9601N CYP-dependent N-dealkylation reaction was also studied and compared with those of l-deprenyl.
  
  
  METHODS
  C57BL/6 mice were treated with PF9601N for 4 days. After CYP content and related monooxygenase activities were assayed in liver microsomes of control and treated animals.
  
  
  RESULTS
  CYP activities, cytochrome b5 content, NADPH-cytochrome P450 reductase and various monooxygenase activities were unaffected by in vivo PF9601N treatment. With microsomes from both control and treated mice, the PF9601N-dealkylation product, FA72, was the only detected metabolite with its formation rate following an hyperbolic, Michaelis-Menten curve. Among various inhibitors, only ketoconazole inhibited the FA72 formation rate, indicating a major involvement for CYP3A. Apparent Km and Vmax values generated by human liver microsomes were similar to those found with mouse microsomes. Ketoconazole inhibition indicates that CYP3A is one of the major enzymes involved in PF9601N metabolism also by human liver microsomes. In mouse liver microsomes, the intrinsic clearance of PF9601N was significantly lower than that of l-deprenyl suggestive of an improved bioavailability for the former.
  
  
  CONCLUSIONS
  The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Farmacologia, Fisiologia e Tossicologia, Università di Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Dragoni
authors.forename: Giada
authors.initials: G
authors.lastname: Materozzi
authors.forename: Federica
authors.initials: F
authors.lastname: Pessina
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.forename: José Luis
authors.initials: JL
authors.lastname: Marco
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; C470996:N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine; D003577:Cytochrome P-450 Enzyme System; D008995:Monoamine Oxidase