title: 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.
authors.affiliation: Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc, Yaizu, Shizuoka 425-0072, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takemura
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kondo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suzumura
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Ogawara
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Watanabe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sako
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000578:Amidines; D000925:Anticoagulants; C574127:N-(4-((1-acetoamidoyl-4-piperidyl)oxy)phenyl)-N-((7-amidino-2-naphtyl)methyl)sulfamoyl acetic acid; D013449:Sulfonamides