Changes in the intestinal absorption mechanism of icariin in the nanocavities of cyclodextrins

Abstract

Icariin is a bioactive herbal ingredient isolated from Herba epimedii, which has been widely used for the treatment of osteoporosis and male sexual dysfunction in traditional Chinese medicine. The major objective of this work is to investigate the different enhancing effects of β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) on the intestinal absorption of icariin, and to identify the molecular mechanisms of this action. Host–guest-type interactions of icariin with cyclodextrins nanocavities were unambiguously demonstrated by the phase-solubility diagram, ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry, and two dimensional proton nuclear magnetic resonance rotating-frame Overhauser effect spectroscopy. These results were further supported using molecular modeling studies. The rat single-pass intestinal perfusion model showed that the absorption of icariin was affected by P-glycoprotein (Pgp). The icariin/HP-β-CD inclusion complex provided greater enhancement in the intestinal absorption than the icariin/β-CD inclusion complex. Therefore, the enhancing effect was involved in a solubilizing effect and/or Pgp inhibitory effect. Finally, fluorescence anisotropy measurements and Pgp adenosine triphosphatase (ATPase) assay demonstrated that β-CD exhibited no effect on Pgp, while HP-β-CD showed inhibition by restraining the Pgp ATPase activity rather than changing the fluidity of cell membrane.

Keywords:

• icariin
• cyclodextrin
• inclusion complex
• molecular modeling
• P-glycoprotein (Pgp)
• intestinal absorption

Acknowledgments

This work was financed by the National Natural Science Foundation of China (No 30570495 and 81173469), and by the Program for New Century Excellent Talents in University (No NCET-09-0899). We thank the Institute of Materia Medica, the Chinese Academy of Medical Sciences, and the Peking Union Medical College for performing the 2D ROESY NMR spectroscopies.

Disclosure

The authors report no conflicts of interest in this work.