An HPLC-MS method for the quantification of new acetylcholinesterase inhibitor PC 48 (7-MEOTA-donepezil like compound) in rat plasma: Application to a pharmacokinetic study.
A simple, rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative determination in rat plasma of a new candidate for AD treatment, namely PC 48 (a 7-MEOTA-donepezil like compound) in rat plasma. Sample preparation involved pH adjustment with sodium hydroxide followed by solvent extraction with ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on an Ascentis Express RP-Amide column (75 mm × 2.1mm, 2.7 μm) with a gradient mobile phase consisting of 0.05 M aqueous formic acid and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry on an LTQ XL system using the MS/MS CID (collision-induced dissociation) mode. The method was linear in the range 0.1-1000 ng/ml (r(2)=0.999) with a lower limit of quantitation of 0.1 ng/mL. Extraction recovery was in the range 63.5-72.1% for PC 48 and 70.5% for reserpine (internal standard, IS). Intra- and inter-day precisions measured as relative standard deviation were below 10.8% and accuracy was from -7.2% to 7.4%. The method was successfully applied to a pharmacokinetic study involving intramuscular application of 3.86 mg/kg PC 48 to rats for the first time. Pharmacokinetic parameters for PC 48 include Cmax 39.09 ± 4.45 ng/mL,Tmax 5.00 ± 3.08 min, AUC0-t 23374 ± 4045 min ng/mL and t1/2 1065 ± 246 min.
['Mzik|Martin|M|', 'Korabecny|Jan|J|', 'Nepovimova|Eugenie|E|', 'Voříšek|Viktor|V|', 'Palička|Vladimir|V|', 'Kuca|Kamil|K|', 'Zdarova Karasova|Jana|J|']
D000544:Alzheimer Disease D000818:Animals D002800:Cholinesterase Inhibitors D002851:Chromatography, High Pressure Liquid D000077265:Donepezil D007189:Indans D016014:Linear Models D008297:Male D010880:Piperidines D051381:Rats D017208:Rats, Wistar D015203:Reproducibility of Results D012680:Sensitivity and Specificity D013619:Tacrine D053719:Tandem Mass Spectrometry
Acetylcholinesterase PC 48 7-MEOTA Alzheimer disease Donepezil HPLC–MS