The selective monoamine oxidase-B (MAO-B) inhibitor, ldeprenyl, is still used for treating Parkinson's patients, however, a disadvantage of its use lies in the formation of l-amphetamine and lmethamphetamine. 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 ldeprenyl suggestive of an improved bioavailability for the former. Conclusion. The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.

Dragoni, S., Materozzi, G., Pessina, F., Frosini, M., Marco, J.L., Unzeta, M., et al. (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 [10.18433/j37p4j].

CYP-dependent metabolism of PF9601N, a new monoamine oxidase-B inhibitor, by C57BL/6 mouse and human liver microsomes

Dragoni, Stefania;Materozzi, Giada;Pessina, Federica;Frosini, Maria;Sgaragli, GIAN PIETRO;Valoti, Massimo
2007-01-01

Abstract

The selective monoamine oxidase-B (MAO-B) inhibitor, ldeprenyl, is still used for treating Parkinson's patients, however, a disadvantage of its use lies in the formation of l-amphetamine and lmethamphetamine. 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 ldeprenyl suggestive of an improved bioavailability for the former. Conclusion. The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.
2007
Dragoni, S., Materozzi, G., Pessina, F., Frosini, M., Marco, J.L., Unzeta, M., et al. (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 [10.18433/j37p4j].
File in questo prodotto:
File Dimensione Formato  
PF9601N_metabolism.pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 282.4 kB
Formato Adobe PDF
282.4 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/22240
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo