Evaluation of factors affecting gastrointestinal absorption of a novel anticoagulant FX-93 for development of oral formulation

Shigeo Takemura, Hiromu Kondo, Kenichi Suzumura, Ken Ichi Ogawara, Shunsuke Watanabe, Kazuhiro Sako, Kazutaka Higaki

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

To find out factors causing the low bioavailability of FX-93, a novel anticoagulant, its solubility, membrane permeability, and the effect of bile salt on the absorption of FX-93 were investigated. The solubility of FX-93 under physiological conditions ranged from 0.3 to 18.3 mg/mL and the dose number was calculated to be 0.02-0.27, suggesting that the intrinsic solubility of FX-93 should not be a limiting factor for oral absorption. Apparent permeability of FX-93 across Caco-2 cell monolayer suggested that its fraction of dose absorbed would range between 30% and 40% in humans. Furthermore, FX-93 was substantially absorbed from each segment of rat intestine. However, the decrease in the gastrointestinal transit rate significantly decreased maximum plasma concentration and area under the plasma concentration-time curve of FX-93 after oral dosing in dogs, suggesting that FX-93 absorption would be suppressed by some components in the small intestinal lumen. An in situ rat administration study indicated that bile significantly decreased the intestinal absorption of FX-93 by two-thirds, which could be attributed to the decrease in FX-93 solubility by the interaction with bile or bile acid. Nuclear magnetic resonance spectroscopy analysis suggested that FX-93 would interact with bile salt between the naphthalene ring of FX-93 and steroidal backbone of bile salt.

Original languageEnglish
Pages (from-to)2134-2142
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume101
Issue number6
DOIs
Publication statusPublished - Jun 2012

Keywords

  • Absorption
  • Bile
  • Caco-2 cells
  • FX-93
  • Gastrointestinal transit
  • Interaction
  • Oral anticoagulant
  • Permeability

ASJC Scopus subject areas

  • Pharmaceutical Science

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