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)

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.

 
  • References

  • 1 Liu JS, Yu CM, Zhou YZ, Han YY, Wu FW, Qi BF, Zhu YL. Study on the chemistry of huperzine-A and huperzine-B. Acta Chim Sin 1986; 44: 1035-1040
  • 2 Lim WH, Goodger JQ, Field AR, Holtum JA, Woodrow IE. Huperzine alkaloids from Australasian and southeast Asian Huperzia . Pharm Biol 2010; 48: 1073-1078
  • 3 Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 2006; 27: 1-26
  • 4 Zhao Q, Tang XC. Effects of huperzine A on acetylcholinesterase isoforms in vitro: comparison with tacrine, donepezil, rivastigmine and physostigmine. Eur J Pharmacol 2002; 455: 101-107
  • 5 Desilets AR, Gickas JJ, Dunican KC. Role of huperzine a in the treatment of Alzheimerʼs disease. Ann Pharmacother 2009; 43: 514-518
  • 6 Gordon RK, Nigam SV, Weitz JA, Dave JR, Doctor BP, Ved HS. The NMDA receptor ion channel: a site for binding of huperzine A. J Appl Toxicol 2001; 21 (Suppl. 01) S47-S51
  • 7 Ha GT, Wong RK, Zhang Y. Huperzine a as potential treatment of Alzheimerʼs disease: an assessment on chemistry, pharmacology, and clinical studies. Chem Biodivers 2011; 8: 1189-1204
  • 8 Chu D, Liu W, Li Y, Li P, Gu J, Liu K. Pharmacokinetics of huperzine A in dogs following single intravenous and oral administrations. Planta Med 2006; 72: 552-555
  • 9 Wang YE, Feng J, Lu WH, Tang XC. Pharmacokinetics of huperzine A in rats and mice. Zhongguo Yao Li Xue Bao 1988; 9: 11-15
  • 10 Wohnsland F, Faller B. High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J Med Chem 2001; 44: 923-930
  • 11 Ovadia O, Greenberg S, Chatterjee J, Laufer B, Opperer F, Kessler H, Gilon C, Hoffman A. The effect of multiple N-methylation on intestinal permeability of cyclic hexapeptides. Mol Pharmacol 2011; 8: 479-487
  • 12 Hess S, Rotshild V, Hoffman A. Investigation of the enhancing mechanism of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate effect on the intestinal permeability of polar molecules utilizing a voltage clamp method. Eur J Pharm Sci 2005; 25: 307-312
  • 13 Lennernas H. Animal data: the contributions of the Ussing Chamber and perfusion systems to predicting human oral drug delivery in vivo . Adv Drug Deliv Rev 2007; 59: 1103-1120
  • 14 Koljonen M, Hakala KS, Ahtola-Satila T, Laitinen L, Kostiainen R, Kotiaho T, Kaukonen AM, Hirvonen J. Evaluation of cocktail approach to standardise Caco-2 permeability experiments. Eur J Pharm Biopharm 2006; 64: 379-387
  • 15 Kimoto T, Takanashi M, Mukai H, Ogawara K, Kimura T, Higaki K. Effect of adrenergic stimulation on drug absorption via passive diffusion in Caco-2 cells. Int J Pharm 2009; 368: 31-36
  • 16 Hess S, Ovadia O, Shalev DE, Senderovich H, Qadri B, Yehezkel T, Salitra Y, Sheynis T, Jelinek R, Gilon C, Hoffman A. Effect of structural and conformation modifications, including backbone cyclization, of hydrophilic hexapeptides on their intestinal permeability and enzymatic stability. J Med Chem 2007; 50: 6201-6211
  • 17 Raiman J, Tormalehto S, Yritys K, Junginger HE, Mönkkönen J. Effects of various absorption enhancers on transport of clodronate through Caco-2 cells. Int J Pharm 2003; 261: 129-136
  • 18 Dixit P, Jain DK, Dumbwani J. Standardization of an ex vivo method for determination of intestinal permeability of drugs using everted rat intestine apparatus. J Pharmacol Toxicol Methods 2012; 65: 13-17
  • 19 Haslam IS, OʼReilly DA, Sherlock DJ, Kauser A, Womack C, Coleman T. Pancreatoduodenectomy as a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue. Biopharm Drug Dispos 2011; 32: 210-221
  • 20 Hwang KM, Liu S. Transdermal rate-controlled delivery of huperzine A for treatment of Alzheimerʼs disease. USPTO, CA: Sagittarius Life Science Corp; 2002 US patent number: 6352715
  • 21 Cao X, Gibbs ST, Fang L, Miller HA, Landowski CP, Shin HC, Lennernas H, Zhong Y, Amidon GL, Yu LX, Sun D. Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm Res 2006; 23: 1675-1686
  • 22 Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev 2001; 46: 27-43
  • 23 Artursson P, Ungell AL, Lofroth JE. Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments. Pharm Res 1993; 10: 1123-1129
  • 24 Linnankoski J, Makela J, Palmgren J, Mauriala T, Vedin C, Ungell AL, Lazorova L, Artursson P, Urtti A, Yliperttula M. Paracellular porosity and pore size of the human intestinal epithelium in tissue and cell culture models. J Pharm Sci 2010; 99: 2166-2175
  • 25 Morris E, Guofeng Y. Drug transporters: molecular characterization and role in drug disposition. West Sussex: Wiley-Interscience; 2007
  • 26 Fricker G, Drewe J, Huwyler J, Gutmann H, Beglinger C. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation. Br J Pharmacol 1996; 118: 1841-1847
  • 27 Horter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev 2001; 46: 75-87
  • 28 Tannergren C, Bergendal A, Lennernas H, Abrahamsson B. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment. Mol Pharmacol 2009; 6: 60-73
  • 29 Tajiri S, Kanamaru T, Yoshida K, Hosoi Y, Fukui S, Konno T, Yada S, Nakagami H. Colonoscopic method for estimating the colonic absorption of extended-release dosage forms in dogs. Eur J Pharm Biopharm 2010; 75: 238-244