Monitoring Plasma Levels of Donepezil, 5-O-Desmethyl-Donepezil, 6-O-Desmethyl-Donepezil, and Donepezil-N-Oxide by a Novel HPLC Method in Patients With Alzheimer Disease. Issue 1 (February 2016)

• Record Type: Journal Article
• Authors: Groppa, Francesca; Coin, Alessandra; De Rosa, Giovanni; Granziera, Serena; Alexopoulos, Chiara; Pamio, Maria Valentina; Padrini, Roberto
• Is Part Of: Therapeutic drug monitoring. Volume 38:Issue 1(2016:Feb.)
• Publication Date: 2016-02
• Subjects: donepezil -- 5-O-desmethyl-donepezil -- 6-O-desmethyl-donepezil -- donepezil-N-oxide -- HPLC assay; Pharmacokinetics -- Periodicals; Patient monitoring -- Periodicals; Drugs -- Analysis -- Periodicals; Body fluids -- Analysis -- Periodicals; Drug Therapy -- Periodicals; Monitoring, Physiologic -- Periodicals; Pharmacology -- Periodicals; 615.7
• DOI: 10.1097/FTD.0000000000000246
• Languages: English
• ISSNs: 0163-4356

Abstract

Abstract : Background: In humans, donepezil (D) is metabolized to 5-O-desmethyl-donepezil (5DD), 6-O-desmethyl-donepezil (6DD), and donepezil-N-oxide (DNox). Although 6DD and DNox are pharmacologically active, the activity of 5DD is unknown. At present, no routine methods are available to detect D and its 3 metabolites simultaneously. In this study, a novel high-performance liquid chromatography method was developed and applied to a population of patients with Alzheimer disease on stable treatment with the drug. Methods: Liquid–liquid extraction from plasma was accomplished by means of a solvent mixture of n-hexane/dichloromethane/ethylacetate (45:40:15) after sample alkalinization. Disopyramide was the internal standard. After evaporation, the residue was reconstituted in 200 μL of mobile phase (acetonitrile 85%:1% acetic acid 15%) and 50 μL was injected into the high-performance liquid chromatography column (X-Terra, RP8; flow: 1 mL/min). Photometric and fluorimetric detectors were used in tandem, to maximize the sensitivity of fluorescent compounds (D, 5DD, and DNox) and also to reveal nonfluorescent compounds (6DD and internal standard). Results: The method was linear in the 10–100 ng/mL concentration range. Imprecision (coefficient of variation) varied between 3.2% and 12.6% and inaccuracy (% mean absolute error) between 1.3% and 13.3%, depending on the compound, concentration, and detection mode. The quantitation limits were 0.1–0.3 ng/mL for fluorescent compounds and 1.2–4.3 ng/mL for photometric compounds. D, 5DD, 6DD, and DNox through concentrations were measured in 54 patients with Alzheimer disease on treatment with D (10 mg q.d.). No interfering peaks by endogenous compounds or coadministered drugs were noted. Plasma concentrations were quite variable among patients (D: 10–106 ng/mL; 5DD: 0.07–2.8 ng/mL; 6DD: 1.2–36 ng/mL; DNox: 0.5–45.4 ng/mL). Of note, in 6 patients, the plasma concentrations of the 2 active metabolites (6DD and DNox) were higher than those of the parent drug. Conclusions: The above method proved to be suitable for therapeutic drug monitoring and may be useful in ascertaining the real contribution of metabolites to the therapeutic effects of donepezil. Abstract : Supplemental Digital Content is Available in the Text.