CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes

Authors

  • Stefania Dragoni Dipartimento de Scienze Diomediche, Sezione di Farmacologia, Fisiologia e Tossicologia, Università di Siena
  • Giada Materozzi Dipartimento de Scienze Diomediche, Sezione di Farmacologia, Fisiologia e Tossicologia, Università di Siena
  • Federica Pessina Dipartimento de Scienze Diomediche, Sezione di Farmacologia, Fisiologia e Tossicologia, Università di Siena
  • Maria Frosini Dipartimento de Scienze Diomediche, Sezione di Farmacologia, Fisiologia e Tossicologia, Università di Siena
  • José Luis Marco Laboratorio de Radicales Libres, Instituto de Chimica Organica General, CSIC, Madrid
  • Mercedes Unzeta Departamento of Bioquimica i Biologia Molecular, Universitat autonoma de Barcelona, Spain
  • Giampietro Sgaragli Dipartimento de Scienze Diomediche, Sezione di Farmacologia, Fisiologia e Tossicologia, Università di Siena
  • Massimo Valoti School of Pharmacy, Siena

DOI:

https://doi.org/10.18433/J37P4J

Abstract

Purpose. 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. Conclusion. The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.

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Author Biography

Massimo Valoti, School of Pharmacy, Siena

Prof Massimo Valoti, Dipartimento di Scienze Biomediche, School of Pharmacy, Siena, Italy, E-mail: valoti@unisi.it

Published

2007-10-12

How to Cite

Dragoni, S., Materozzi, G., Pessina, F., Frosini, M., Marco, J. L., Unzeta, M., … Valoti, M. (2007). CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes. Journal of Pharmacy & Pharmaceutical Sciences, 10(4), 473–485. https://doi.org/10.18433/J37P4J

Issue

Section

Pharmaceutical Sciences; Review Articles