Development of an LC-MS/MS method for simultaneous determination of memantine and donepezil in rat plasma and its application to pharmacokinetic study.
Recently, a fixed dose combination (FDC) of memantine (MM) and donepezil (DPZ) has been approved for the treatment of Alzheimer's disease (AD). In the present work, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of MM and DPZ was developed and validated in rat plasma over the linearity range of 0.2-400ng/mL using amantadine (AM) as an internal standard. Both the analytes and IS were extracted using one step liquid-liquid extraction procedure. The analytes were separated on C18 reversed phase column with mobile phase consisting of a mixture of methanol and 10mM ammonium acetate, pH 5 (92:8 v/v) at a flow rate of 0.7mL/min. The detection of the analytes was done on triple quadrupole mass spectrometer operated in positive electrospray ionization mode (ESI) and quantified using multiple reaction monitoring (MRM). The method was fully validated in terms of linearity, accuracy, precision, recovery, matrix effect, dilution integrity, carry-over effect and stability. The within- and between-run precisions were <10% and accuracy was all within ±10%. The mean recovery of MM and DPZ was found to be greater than 80%. The % RSD value at higher as well as lower concentration was well within the acceptable range (±15%) in all the stability experiments. The method was successfully applied to the oral pharmacokinetics and drug-drug interaction study of MM and DPZ in male Sprague Dawley (SD) rats.
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226032, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
Manisha
M
Bhateria
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226032, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
Rachumallu
R
Ramakrishna
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Rae Bareli, Uttar Pradesh, India.
Dora Babu
DB
Pakala
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226032, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India. Electronic address: rabi_bhatta@cdri.res.in.
Rabi Sankar
RS
Bhatta
D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D000077265:Donepezil; D007189:Indans / Q000097:blood* / Q000493:pharmacokinetics; D057230:Limit of Detection; D008559:Memantine / Q000097:blood* / Q000493:pharmacokinetics; D018697:Nootropic Agents / Q000097:blood* / Q000493:pharmacokinetics; D010880:Piperidines / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D008559:Memantine
Alzheimer’s disease; Donepezil; Drug interaction; LC–MS/MS; Memantine; Pharmacokinetics