Donepezil - How It Works
Clinical pharmacology details from the US FDA-approved label: how Donepezil works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's disease attribute some of them to a deficiency of cholinergic neurotransmission.
Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function.
This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase.
There is no evidence that donepezil alters the course of the underlying dementing process.
12.2 Pharmacokinetics Pharmacokinetics of donepezil are linear over a dose range of 1 to 10 mg given once daily.
The rate and extent of absorption of donepezil hydrochloride tablets are not influenced by food.
Based on population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer’s disease, following oral dosing, peak plasma concentration is achieved for donepezil hydrochloride 23 mg tablets in approximately 8 hours, compared with 3 hours for donepezil hydrochloride 10 mg tablets.
Peak plasma concentrations were almost 2-fold higher for donepezil hydrochloride 23 mg tablets than donepezil hydrochloride 10 mg tablets.
The elimination half life of donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13 to 0.19 L/hr/kg.
Following multiple dose administration, donepezil accumulates in plasma by 4 to 7 fold, and steady state is reached within 15 days.
The steady state volume of distribution is 12 to 16 L/kg.
Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha 1 - acid glycoprotein (about 21%) over the concentration range of 2 to 1000 ng/mL.
Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified.
Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation.
Following administration of 14 C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil.
Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug.
Examination of the effect of CYP 2D6 genotype in Alzheimer’s patients showed differences in clearance values among CYP 2D6 genotype subgroups.
When compared to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance.
These results suggest CYP 2D6 has a minor role in the metabolism of donepezil.
Hepatic Disease: In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil hydrochloride was decreased by 20% relative to 10 healthy age- and sex-matched subjects.