Absorption, Distribution and Excretion Pattern of Oral and Transdermal Donepezil Hydrochloride after Single and Repeated Administration to the Rat

Susan R,Meier Davis

doi:10.4172/2157-7609.1000123

Abstract

Donepezil hydrochloride formulated in a transdermal patch for weekly administration is an alternative to the approved daily oral tablet. Transdermal delivery has a locally high concentration at the application site causing potential safety issues. To assess the skin exposure for safety evaluation, studies were performed comparing the donepezil transdermal patch with an oral donepezil dose previously tested in a carcinogenicity study, in which no test article-induced tumors were found. Quantitative Whole Body Autoradiography (QWBA) comparison in Long-Evans rats administered 14C-donepezil either as single oral dose (30 mg/kg) or a 24-hour transdermal patch (~60 mg/kg) revealed similar organ distribution, including skin. Pigmented tissue, namely, skin and eye showed sustained labeling over 7-10 days, suggesting melanin binding. Subsequently, a 14C-donepezil study in Long-Evans rats comparing seven daily oral doses (10-30 mg/kg) with a seven-day transdermal patch (~40 mg/kg) again revealed similar tissue distributions between the two delivery methods, however, skin not directly exposed to the transdermal patch had less label as compared to both unpigmented and pigmented skin after oral dosing. Similarly, eye concentrations generally had higher label after oral dosing as compared to the transdermal administration. Upon patch removal, the non-viable stratum corneum under the dose-site contained the majority of the label with the underlying skin layers returning to baseline levels within 5 and 7 days for unpigmented and pigmented skin, respectively, illustrating dermal clearance. Skin structures were comparably labeled after oral and transdermal administration, as evidenced by microautoradioagraphy.

Highlights

Donepezil hydrochloride, an acetylcholinesterase inhibitor, is approved for the symptomatic treatment of mild, moderate to severe cases of Alzheimer’s disease
A donepezil transdermal patch was evaluated for absorption, distribution and excretion patterns relative to the approved oral route to determine potential differences and feasibility of the transdermal route of administration
The calculated mean dose of 14C-donepezil administered via the transdermal route was between 61.3 ± 14.7 mg/kg and 66.7 ± 19.6 mg/kg, equivalent to a radiochemical dose of 6.74 ± 1.60 μCi/animal and 7.30 ± 2.19 μCi/animal and, respectively

Summary

Introduction

An acetylcholinesterase inhibitor, is approved for the symptomatic treatment of mild, moderate to severe cases of Alzheimer’s disease. Given that memory deficits are one of the symptoms of Alzheimer’s disease, a multi-day transdermal patch could enhance patient compliance. Transdermal patches have additional advantages in that the treatment compliance can be visualized, there is circumvention of gastrointestinal absorption and hepatic first-pass metabolism and a minimization of adverse effects secondary to peak plasma drug concentrations. The common adverse effects of transdermal patches, namely, irritation and sensitization, tend to decrease in severity and incidence with age [2,3]. A donepezil transdermal patch was evaluated for absorption, distribution and excretion patterns relative to the approved oral route to determine potential differences and feasibility of the transdermal route of administration

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