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

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. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2134–2142, 2012