In vitro kinetic study of donepezil N- oxide metabolites

Faris T Abachi,Riyath A Atto,Ammar B Behnan

doi:10.33899/iphr.2011.49912

Abstract

Objective: The aim of this study was to examine the metabolism of donepezil via N – oxidation of donepezil HCl in vitro, and the kinetic studies at a temperature similar to that of the human body. Methods: Direct reaction of donepezil with hydrogen peroxide and formic acid at room temperature, the N – oxide undergoes a series of rearrangements, the reaction was followed by ultraviolet at λmax= 268 nm at 37 °C. The donepezil N- oxide was also tested as potential cholinesterase inhibitor using electrometric for cholinesterase determination. Results: According to the present work , the structure of donepzil N- oxide was elucidated using spectroscopic analysis , also , in vitro kinetic study at 37 °C using ultraviolet spectrophotometer at λmax = 268 nm showed that the reaction proceeded at a first order reaction . Biologically, the compound was found to inhibit both plasma and erythrocyte cholinesterase activities in vitro .. Conclusion: We concluded that the N- oxide of denepezil undergoes a series of rearrangements, the reaction followed first order at 37 °C. It has a potential anticholinesterase activity

Highlights

Initially concentrated on acetylcholinesterase (AchE) inhibition since this is the main enzyme involved in the hydrolysis of Ach in the normal brain[6]
Donepezil N- oxide was prepared in vitro as route of metabolism via N-oxidation, and the structure was identified by using physical and spectroscopic techniques. The order of this reaction can be determined by using kinetic measurements at 37 °C
The 1H experiments were performed on Brucker 400 MHz (France) and the 13C and DEPT NMR experiments were performed on a 200 MHz instrument model 2000 at 25 ̊C in CDCl3

Summary

Objective

The aim of this study was to examine the metabolism of donepezil via N – oxidation of donepezil HCl in vitro, and the kinetic studies at a temperature similar to that of the human body. Methods: Direct reaction of donepezil with hydrogen peroxide and formic acid at room temperature, the N – oxide undergoes a series of rearrangements, the reaction was followed by ultraviolet at λmax= 268 nm at 37 ̊C. Conclusion: We concluded that the N- oxide of denepezil undergoes a series of rearrangements, the reaction followed first order at 37 ̊C. ‫الحمراء وذلك بتغير درجة ألبها‬ ‫ ويعاني إعادة ترتيب‬، ‫ نستنتج من هذه الدراسة بان ايض الدونيبيزيل عن طريق أآسدة ذرة النتروجين‬:‫النتائج‬ ‫ وتم اختبار اوآسيد النتروجين خارج جسم الكائن‬،‫م‬° ٣٧ ‫جزئي ومتابعة حرآية التفاعل عند درجة حرارة‬. Depletion of acetylcholine (Ach) represents the most important event but other neurotransmitters such as serotonin (5HT), noradrenalin (NA), dopamine (DA), glutamate and substance P are involved[3,4,5]

Cholinergic therapy for AD initially concentrated on

Results and Discussion

ChE in erythrocyte at concentrations of

Bioorganic Med Chem Lett

Chem Phys Lip