alexa Comparison of Metabolism of Donepezil in Rat, Mini-Pig and Human, Following Oral and Transdermal Administration, and in an In Vitro Model of Human Epidermis | Abstract
ISSN: 2157-7609

Journal of Drug Metabolism & Toxicology
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Research Article

Comparison of Metabolism of Donepezil in Rat, Mini-Pig and Human, Following Oral and Transdermal Administration, and in an In Vitro Model of Human Epidermis

S. R. Meier-Davis1*, R. Murgasova2, C. Toole3, F. M. Arjmand1, L. Diehl4, B. Cayme1, J. Wen1, J. Shudo1 and T. Nagata1

1Teikoku Pharma USA, Inc., USA

2Charles River Preclinical Services, Montreal, Senneville (Quebec), Canada

3CeeTox, Inc., Kalamazoo, Michigan, USA

4Charles River Laboratories, Spencerville, OH, USA

*Corresponding Author:
Susan Meier-Davis
1718 Ringwood Avenue
San Jose, CA 95131, Canada
Tel: +408-501-1829
Fax: +408-501-1929
E-mail: [email protected]

Received Date: February 28, 2012; Accepted Date: July 25, 2012; Published Date: July 27, 2012

Citation: Meier-Davis SR, Murgasova R, Toole C, Arjmand FM, Diehl L, et al. (2012) Comparison of Metabolism of Donepezil in Rat, Mini-Pig and Human, Following Oral and Transdermal Administration, and in an in vitro Model of Human Epidermis. J Drug Metab Toxicol 3:129. doi: 10.4172/2157-7609.1000129

Copyright: © 2012 Meier-Davis SR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Donepezil hydrochloride is a centrally acting, reversible acetyl cholinesterase inhibitor approved for Alzheimer’s disease therapy. Donepezil is marketed as an oral tablet but a transdermal patch may have advantages as an alternate therapy. To determine whether the transdermal route alters known donepezil metabolism, this study compared plasma metabolites of donepezil hydrochloride with two routes of drug delivery, transdermal and oral, in three species; rat, mini-pig and human. The utility of a reconstituted human epidermis (RHE) in vitro model for transdermal drug biotransformation was also evaluated. In addition to donepezil, structures from three metabolic pathways were detectable in each matrix: 1) O demethylation (M1/M2; 2) N-dealkylation (M4); 3) N-oxidation (M6) utilizing LC/quadrupole–Ion trap MS/MS. In rats and humans, including RHE, the mean concentration levels of the donepezil and metabolites for both routes were found in the following order: donepezil>M4>M6>isomeric M1/M2 whilst in the pig, the order was the following: donepezil>M6>isomeric M1/M2>M4. Overall, there were no substantial differences in the plasma profiles between the rat and human. Donepezil metabolites were detectable in mini-pigs after both oral and transdermal administration, however, the concentrations varied from both rat and human. RHE showed quantitative and qualitative similarities between the metabolites produced in vitro with those found in human plasma after transdermal application. Thus, the data from the present study demonstrate that similar metabolites are found between the three species with rat most closely resembling humans and that the RHE model is a potentially valuable model to predict dermal metabolism.

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