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Planta Med 2013; 79(03/04): 259-265
DOI: 10.1055/s-0032-1328128
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Transepithelial Transport of a Natural Cholinesterase Inhibitor, Huperzine A, along the Gastrointestinal Tract: the Role of Ionization on Absorption Mechanism

Gregory Burshtein
Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
,
Michael Friedman
Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
,
Sarit Greenberg
Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
,
Amnon Hoffman
Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
› Author Affiliations
Further Information

Publication History

received 20 May 2012
revised 04 December 2012

accepted 07 December 2012

Publication Date:
23 January 2013 (online)

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Abstract

During recent years there has been increasing interest in the Lycopodium alkaloid huperzine A as a potential therapeutic agent for neurodegenerative diseases. This study aimed to characterize huperzine Aʼs permeability across the enterocyte barrier along the gastrointestinal tract with an emphasis on the effect of ionization on the drug absorption. Intestinal permeability of huperzine A was evaluated by in vitro Caco-2 and parallel artificial membrane permeation assay models and by the ex vivo Ussing chamber model. The permeability rate was strongly dependent on the degree of ionization and increased with elevation of the donor medium pH in all studied models. The transport of the unionized fraction was similar to the permeability of the markers for passive transcellular diffusion. Addition of the paracellular permeability modulator palmitoylcarnitine in the Caco-2 model led to significant enhancement in the permeability of the ionized huperzine A fraction. No evidence of active transport of huperzine A was detected in this study. The Ussing chamber model experiments showed similar drug permeability along the entire rat intestine. In conclusion, huperzine A permeates the intestinal border mainly by passive transcellular diffusion whereas some fraction, dependent on the degree of huperzine A ionization, is absorbed by the paracellular route. Huperzine Aʼs permeability characteristics pave the way to the development of its oral extended release dosage form. The specific population of the potential users of huperzine A and the high potency of this molecule support the rationale for such a delivery.

Key words

huperzine A - permeability - PAMPA - Caco-2 - Ussing chamber - Huperzia serrate - Lycopodiaceae
 

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