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. Special Populations: Hepatic Disease: In a study of 11 patients with stable alcoholic cirrhosis, the clearance of ARICEPTŪ was decreased by 20% relative to 11 healthy age and sex matched subjects. Renal Disease: In a study of 11 patients with moderate to severe renal impairment (ClCr < 18 mL/min/1.73 m2) the clearance of ARICEPTŪ did not differ from 11 age and sex matched healthy subjects. Age: No formal pharmacokinetic study was conducted to examine age related differences in the pharmacokinetics of ARICEPTŪ. However, mean plasma ARICEPTŪ concentrations measured during therapeutic drug monitoring of elderly patients with Alzheimer?s Disease are comparable to those observed in young healthy volunteers. Gender and Race: No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of ARICEPTŪ. However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese and Caucasians) did not affect the clearance of ARICEPTŪ. | ||||
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