CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes
DOI:
https://doi.org/10.18433/J37P4JAbstract
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.Downloads
Downloads
Published
How to Cite
Issue
Section
License
This is an open access journal with free of charge non-commercial download. At the time of submission, authors will be asked to transfer the copyright to the accepted article to the Journal of Pharmacy and Pharmaceutical Sciences. The author may purchase the copyright for $500 upon which he/she will have the exclusive copyright to the article. Nevertheless, acceptance of a manuscript for publication in the Journal is with the authors' approval of the terms and conditions of the Creative Commons copyright license Creative Common license (Attribution-ShareAlike) License for non-commercial uses.
CLOCKSS system has permission to collect, preserve, and serve this Archival Unit.