Donepezil pharmacokinetics and molecular data

Pharmacokinetics
Mechanism Absorption Plasma protein binding Metabolism Clearance
 * Hepatic disease
 * Renal disease
 * Age
 * Gender and race

Mechanism
Aricept® (donepezil hydrochloride) is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2,3-dihydro-5,6-dimethoxy-2-Return to top''

Absorption
Aricept® ODT is bioequivalent to Aricept® Tablets. Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1-10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of Aricept® Tablets. A food effect study has not been conducted with Aricept® ODT; however, the effect of food with Aricept® ODT is expected to be minimal. Aricept® ODT can be taken without regard to meals. Return to top

Plasma protein binding
The elimination half life of donepezil is about 70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4-7 fold and steady state is reached within 15 days. The steady state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1 - acid glycoprotein (about 21%) over the concentration range of 2-1000 ng/mL. Return to top

Metabolism
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 14C-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. Return to top

Hepatic disease
In a study of 10 patients with stable alcoholic cirrhosis, the clearance of Aricept® was decreased by 20% relative to 10 healthy age and sex matched subjects. Return to top

Renal disease
In a study of 11 patients with moderate to severe renal impairment (ClCr< 18 mL/min/1.73 m2) the clearance of Aricept® did not differ from 11 age and sex matched healthy subjects. Return to top

Age
No formal pharmacokinetic study was conducted to examine age related differences in the pharmacokinetics of Aricept®. However, mean plasma Aricept® concentrations measured during therapeutic drug monitoring of elderly patients with Alzheimer's Disease are comparable to those observed in young healthy volunteers. Return to top

Gender and race
No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of Aricept®. However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese and Caucasians) did not affect the clearance of Aricept®. Return to top