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

OBJECTIVES: 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 11 C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11 C-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 11 C-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 11 C-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, 11 C-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 11 C-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 11 C-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 11 C-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 11 C-DNP PET studies, combined with the oral administration of DNP.