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 ß-cyclodextrin (ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-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-ß-CD inclusion complex provided greater enhancement in the intestinal absorption than the icariin/ß-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 ß-CD exhibited no effect on Pgp, while HP-ß-CD showed inhibition by restraining the Pgp ATPase activity rather than changing the fluidity of cell membrane.
Subject(s)
Flavonoids/chemistry , Flavonoids/pharmacokinetics , Intestinal Absorption/drug effects , Nanostructures/chemistry , beta-Cyclodextrins/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Analysis of Variance , Animals , Calorimetry, Differential Scanning , Drug Interactions , Male , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Rats , Rats, Sprague-Dawley , Solubility , Spectrum Analysis , beta-Cyclodextrins/chemistryABSTRACT
In the title compound, C(19)H(17)ClN(2)O(2), the pyrazole ring makes dihedral angles of 6.97â (5) and 79.25â (1)°, respectively, with the phenyl and chlorophenyl rings, respectively. In the crystal, C-Hâ¯O hydrogen bonds are observed.
ABSTRACT
The purpose of this work is to investigate the effect of the genipin/hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex on the intestinal absorption of genipin and identify its mechanism of action. The phase solubility profile was classified as A(L) type, indicating the formulation of a 1:1 stoichiometry inclusion complex. Fourier transform infrared spectroscopy, Differential scanning calorimetry, X-ray powder diffractometry, and (1)H nuclear magnetic resonance (NMR) and two-dimensional (2D) (1)H rotating-frame Overhauser enhancement (ROESY) NMR spectroscopies further confirmed the formulation of the inclusion complex with superior dissolution properties than the drug alone. The results of single-pass intestinal perfusion showed that the intestinal absorption of genipin was affected by P-glycoprotein (Pgp). The absorption rate and permeability value of the inclusion complex were significantly higher than the free drug, suggesting that its enhancing effect was involved in its solubilizing effect and Pgp inhibitory effect. The mechanisms of HP-ß-CD on Pgp inhibition were demonstrated by restraining the Pgp ATPase activity rather than changing the fluidity of the cell membrane.
