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

Susan R. Meier-Davis, Marie-Eve Rodrigue, Masahiro Yamaji, Yoshiko Katori-Stowell, Jianye Wen, Fatima M. Arjmand, Jutaro Shudo and Tetsuto Nagata

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.