Whole body pharmacokinetics of C-11 donepezil hydrochloride in humans: A positron emission tomography study

Objectives Donepezil hydrochloride (DNP) is acetylcholine esterase inhibitor prescribed in patients with Alzheimer’s disease. Its accumulation to brain was investigated by means of positron emission tomography (PET) with ¹¹C-DNP (Okamura et al., Br J Clin Pharmacol, 2008). However, whole body pharmacokinetics has not been evaluated in humans. We aimed to reveal ¹¹C-DNP pharmacokinetics after oral administration of microdose and therapeutic dose DNP.

Methods Four female volunteers, age ranging from 49 to 65 year (mean, 57.3 year), were enrolled. Their normality was examined by blood tests (hematological exam, liver and renal function), ECG, brain MR (T1WI, T2WI, and MRA). Each subject (n=4) took DNP (30μg;1% of therapeutic dose) orally. After 2.5 hour, ¹¹C-DNP(270∼370MBq, less than 10μg) was intravenously infused for 2min. Whole body scanning was done 60 min after injection for 20 min. After 2 weeks or more, each subject (n=3) took DNP (1mg; therapeutic dose). Same scan procedure was repeated. Standardized uptake value (SUV) was measured in various organs.

Results When ¹¹C-DNP was intravenously administered in association with oral pretreatment of microdose and therapeutic dose DNP, liver (SUV=12.9±3.0 in microdoe study and 15.6±0.8 in therapeutic dose study, respectively), pancreas (7.6±0.9 and 6.4±0.8), myocardium (3.3±0.7 and 2.9±0.4), and bone marrow (1.9±0.1 and 2.2±0.3)showed increased radioactivity in normal humans. No significant difference was found in SUV values between microdose and therapeutic dose studies in these organs. Brain (0.9±0.1 and 0.8±0.0) showed lower radioactivity than these organs.

Conclusions ¹¹C-DNP accumulated to various non-target organs. The results may indicate that adverse effects of DNP such as bradycardia are due to the DNP accumulation outside the central nervous system.