title: 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.
abstract: 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.
authors.affiliation: Institute of Clinical Biochemistry and Diagnostic, University Hospital, Hradec Kralove, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Mzik
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Brno, Czech Republic; Biomedical Research Center, University Hospital, Hradec Kralove, Czech Republic.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Nepovimova
authors.affiliation: Institute of Clinical Biochemistry and Diagnostic, University Hospital, Hradec Kralove, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Voříšek
authors.affiliation: Institute of Clinical Biochemistry and Diagnostic, University Hospital, Hradec Kralove, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Palička
authors.affiliation: Biomedical Research Center, University Hospital, Hradec Kralove, Czech Republic; Department of Cellular Biology and Pharmacology, College of Medicine, International University, Miami, FL, USA.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Brno, Czech Republic; Biomedical Research Center, University Hospital, Hradec Kralove, Czech Republic. Electronic address: zdarova.jana@gmail.com.
authors.forename: Jana
authors.initials: J
authors.lastname: Zdarova Karasova
mesh_terms: D000544:Alzheimer Disease; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D000077265:Donepezil; D007189:Indans / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D016014:Linear Models; D008297:Male; D010880:Piperidines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013619:Tacrine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D013619:Tacrine; C016222:7-methoxytacrine; D000077265:Donepezil
keywords: 7-MEOTA; Acetylcholinesterase; Alzheimer disease; Donepezil; HPLC–MS; PC 48