title: Cyclodextrins improve oral absorption of a novel factor Xa inhibitor by interfering with interaction between the drug and bile acids in rats.
abstract: OBJECTIVE
  Poor oral absorption of a factor Xa inhibitor, DX-9065, is partly due to the interaction with bile acids in the gastrointestinal tract. The aim of this study is to improve the oral bioavailability of DX-9065 by cyclodextrins (CyDs) capable of interfering with such interaction.
  
  
  METHODS
  The abilities of the CyDs to interfere with the interaction between DX-9065 and sodium chenodeoxycholate were evaluated using equilibrium dialysis. The interaction between DX-9065 and the CyDs was studied spectroscopically. Effects of the CyDs on the oral absorption of DX-9065 were examined in rats.
  
  
  RESULTS
  Hydroxypropyl-β-CyD and γ-CyD were effective in interfering with the interaction between DX-9065 and sodium chenodeoxycholate as a representative bile acid. Spectroscopic studies revealed that DX-9065 was included into the CyD cavity to form inclusion complexes in an acidic medium. With dissociation of the carboxyl group of DX-9065 in a neutral medium, the stability of the complexes was decreased to such an extent that DX-9065 in the cavity is replaced with co-existing bile acids. The average area under the plasma concentration-time curve value after oral administration of DX-9065 with hydroxypropyl-β-CyD was 2.5 times higher than that of DX-9065 alone with a statistical difference in rats.
  
  
  CONCLUSIONS
  We suggest that the CyDs are useful in designing oral formulations of DX-9065 with an improved bioavailability.
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co. Ltd, Tokyo, Japan.
authors.forename: Yoshimine
authors.initials: Y
authors.lastname: Fujii
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takako
authors.initials: T
authors.lastname: Ishiguro
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakuma
authors.forename: Kaneto
authors.initials: K
authors.lastname: Uekama
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D004347:Drug Interactions; D065427:Factor Xa Inhibitors; D006863:Hydrogen-Ion Concentration; D008297:Male; D009281:Naphthalenes / Q000378:metabolism / Q000493:pharmacokinetics*; D011422:Propionates / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047392:beta-Cyclodextrins / Q000494:pharmacology*; D047408:gamma-Cyclodextrins / Q000494:pharmacology*
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D011422:Propionates; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; D002635:Chenodeoxycholic Acid
keywords: DX-9065; bile acid; cyclodextrin; intermolecular interaction; oral absorption