Transepithelial transport of a natural cholinesterase inhibitor, huperzine a, along the gastrointestinal tract: The role of ionization on absorption mechanism

Gregory Burshtein, Michael Friedman, Sarit Greenberg, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 As 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 As 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.

Original languageAmerican English
Pages (from-to)259-265
Number of pages7
JournalPlanta Medica
Volume79
Issue number3-4
DOIs
StatePublished - 2013

Bibliographical note

Funding Information:
This is a project initiated by the ESMO Translational Research and Precision Medicine Working Group. We would also like to thank ESMO leadership for their support in this manuscript. This study is a project funded by European Society for Medical Oncology (no grant number applies). European Society for Medical Oncology, CM has received personal/consultancy fees from Axiom Healthcare Strategies, Cor2Ed, Bayer and Daiichi-Sankyo. MS received research funds from Puma Biotechnology, Daiichi-Sankyo, Immunomedics and Menarini Ricerche, honoraria from ADC Pharma and Menarini Ricerche and is a cofounder of Medendi Medical Travel. AJI is a founder and equity holder in ArcherDx, has received research funds from Blueprint Medicines, and is a consultant for Chugai, DebioPharm, Constellation, Roche and Pfizer. ML has received advisory board compensation from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Takeda and Bayer, clinical research support from LOXO Oncology, and pre-clinical research support from Helsinn Healthcare. JFH has received honoraria from Medscape, Axiom Biotechnologies and Cor2Ed, as well as research funding from Bayer. FL-R has received research funding from Thermo Fisherand Roche, as well as honoraria from Bayer, Thermo Fisher and Roche. JSR-F reports personal/consultancy fees from VolitionRx, Page.AI, Goldman Sachs, Grail, Ventana Medical Systems, Roche and Genentech. All remaining authors have declared no conflicts of interest.

Funding Information:
CM has received personal/consultancy fees from Axiom Healthcare Strategies, Cor2Ed, Bayer and Daiichi-Sankyo. MS received research funds from Puma Biotechnology, Daiichi-Sankyo, Immunomedics and Menarini Ricerche, honoraria from ADC Pharma and Menarini Ricerche and is a cofounder of Medendi Medical Travel. AJI is a founder and equity holder in ArcherDx, has received research funds from Blueprint Medicines, and is a consultant for Chugai, DebioPharm, Constellation, Roche and Pfizer. ML has received advisory board compensation from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Takeda and Bayer, clinical research support from LOXO Oncology, and pre-clinical research support from Helsinn Healthcare. JFH has received honoraria from Medscape, Axiom Biotechnologies and Cor2Ed, as well as research funding from Bayer. FL-R has received research funding from Thermo Fisherand Roche, as well as honoraria from Bayer, Thermo Fisher and Roche. JSR-F reports personal/consultancy fees from VolitionRx, Page.AI, Goldman Sachs, Grail, Ventana Medical Systems, Roche and Genentech. All remaining authors have declared no conflicts of interest.

Funding Information:
This study is a project funded by European Society for Medical Oncology (no grant number applies).

Keywords

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

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