Whole-Body Distribution of Donepezil as an Acetylcholinesterase Inhibitor after Oral Administration in Normal Human Subjects: A 11C-donepezil PET Study

Document Type: Original Article

Authors

1 Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine Osaka University Graduate School of Medicine Immunology Frontier Research Center

2 Department of Molcular Imaging in Medicine, Osaka University Graduate School of Medicine Department of Molcular Imaging in Medicine, Osaka University Graduate School of Medicine

3 Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine Department of Molcular Imaging in Medicine, Osaka University Graduate School of Medicine

4 Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine Osaka University Hospital

5 Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine

6 Department of Nuclear Medicine and Tra cer Kinetics, Osaka University Graduate School of Medicine Department of Molcular Imaging in Medicine, Osaka University Graduate School of Medicine

Abstract

Objective(s): It is difficult to investigate the whole-body distribution of an orally administered drug by means of positron emission tomography (PET), owing to the short physical half-life of radionuclides, especially when 11C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11C-DNP PET imaging, combined with the oral administration of pharmacological doses of DNP.
Methods: We studied 14 healthy volunteers, divided into group A (n=4) and group B (n=10). At first, we studied four females (mean age: 57.3±4.5 y), three of whom underwent 11C-DNP PET scan at 2.5 h after the oral administration of 1 mg and 30 μg of DNP, respectively, while one patient was scanned following the oral administration of 30 μg of DNP (group A). Then, we studied five females and five males (48.3±6.1 y), who underwent 11C-DNP PET scan, without the oral administration of DNP (group B). Plasma DNP concentration upon scanning was measured by tandem mass spectrometry. Arterialized venous blood samples were collected periodically to measure plasma radioactivity and metabolites. In group A, 11C-DNP PET scan of the brain and whole body continued for 60 and 20 min, respectively. Subjects in group B underwent sequential whole-body scan for 60 min. The regional uptake of 11C-DNP was analyzed by measuring the standard uptake value (SUV) through setting regions of interest on major organs with reference CT.
Results: In group A, plasma DNP concentration was significantly correlated with the orally administered dose of DNP. The mean plasma concentration was 2.00 nM (n=3) after 1 mg oral administration and 0.06 nM (n=4) after 30 μg oral administration. No significant difference in plasma radioactivity or fraction of metabolites was found between groups A and B. High 11C-DNP accumulation was found in the liver, stomach, pancreas, brain, salivary glands, bone marrow, and myocardium in groups A and B, in this order. No significant difference in SUV value was found among 11C-DNP PET studies after the oral administration of 1 mg of DNP, 30 μg of DNP, or no DNP.
Conclusion: The present study demonstrated that the whole-body distribution of DNP after the oral administration of pharmacological doses could be evaluated by 11C-DNP PET studies, combined with the oral administration of DNP.

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1. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368(9533):387-403.
2. Mihara M, Ohnishi A, Tomono Y, Hasegawa J, Shimamura Y, Yamazaki K, et al. Pharmacokinetics of E2020, a new compound for Alzheimer’s disease, in healthy male volunteers. Int J Clin Pharmacol Ther Toxicol. 1993;31(5):223-9.
3. Ohnishi A, Mihara M, Kamakura H, Tomono Y, Hasegawa J, Yamazaki K, et al. Comparison of the pharmacokinetics of E2020, a new compound for Alzheimer’s disease, in healthy young and elderly subjects. J Clin Pharmacol. 1993;33(11):1086-91.
4. Okamura N, Funaki Y, Tashiro M, Kato M, Ishikawa Y,Maruyama M, et al. In vivo visualization of donepezil binding in the brain of patients with Alzheimer’s disease. Br J Clin Pharmacol. 2008;65(4):472-9.
5. Hiraoka K, Okamura N, Funaki Y, Watanuki S, Tashiro M, Kato M, et al. Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-11C-methoxy] donepezil. Neuroimage. 2009;46(3):616-23.
6. Gjerloff T, Jakobsen S, Nahimi A, Munk OL, Bender D, Alstrup AK, et al. In vivo imaging of human acetylcholinesterase density in peripheral organs using 11C-donepezil: dosimetry, biodistributio, and kinetic analysis. J Nucl Med. 2014;55(11):1818-24
7. Gjerloff T, Fedorova T, Knudsen K, Munk OL, Nahimi A, Jacobsen S, et al. Imaging acetylcholinesterase density in peripheral organs in Parkinson’s disease with 11C-donepezil PET. Brain. 2015;138(Pt 3):653-63.
8. Funaki Y, Kato M, Iwata R, Sakurai E, Tashiro M, Ido T, et al. Evaluation of the binding characteristics of [5-(11)C-methoxy] donepezil in the rat brain for in vivo visualization of acetylcholinesterase. J Pharmacol Sci. 2003;91(2):105-12.
9. Matsumoto K, Kitamura K, Mizuta T, Tanaka K, Yamamoto S, Sakamoto S, et al. Performance characteristics of a new 3-dimensional continuousemission and spiral-transmission high sensitivity and high-resolution PET camera evaluated with the NEMA NU 2-2001 standard. J Nucl Med. 2006;47(1):83–90.
10. Tanaka E, Kudo H. Subset-dependent relaxation in block-iterative algorithms for image reconstruction in emission tomography. Phys Med Biol.2003;48(10):1405–22.
11. Ravic M, Warrington S, Boyce M, Dunn K, Johnston A. Repeated dosing with donepezil does not affect the safety, tolerability or pharmacokinetics of single-dose thioridazine in young volunteers. Br J
Clin Pharmacol. 2004;58(Suppl 1):34–40.
12. Watabe T, Naka S, Ikeda H, Horitsugi G, Kanai Y, Isohashi K, et al. Distribution of intravenously administered acetylcholinesterase inhibitor and acetylcholine esterase activity in the adrenal gland:
11C-Dopenezil PET study in the normal rat. PLoS One. 2014; 9(9): e107427.
13. EU/EMEA/CPMP: Position Paper on non-clinical safety studies to support clinical trials with a single microdose. The European Medicines Agency (EMEA), Evaluation of Medicines for Human Use, CPMP/ SWP/2599/02 London, January 23, 2003.
14. US FDA: Guidance for Industry, Investigatorsand Reviewers, Exploratory IND Studies, US Department of Health and Human Services, FDA, CDER; January 12, 2006.
15. Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol. 2000;27(7):661-70.