LC determination of YM466, a new factor Xa inhibitor, in rat and dog plasma

Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug–bile interaction

“…The obtained C max , 1.01 ± 0.05 μg/mL, and AUC 0–1 h , 0.78 ± 0.12 μg h/mL, of phenol red administered with AAM copolymer E and Tween 80 were not significantly different from those for phenol red alone ( C max , 1.49 ± 1.20 μg/mL; AUC, 0.83 ± 0.54 μg h/mL), indicating that either AAM copolymer E or Tween 80 does not affect the intestinal membrane permeability via passive diffusion at all. Although detailed absorption mechanism of YM466 remains to be clarified, this drug would be considered to be absorbed via passive diffusion from its hydrophilic property with a calculated Log P value less than −47 and the preliminary result that there are no significant difference in membrane permeability of YM466 between from apical to basal side and basal to apical side in Caco‐2 cells (data not shown). These results would confirm that the enhancement of oral absorption of YM466 by the liquid formulation (P–D ratio 3, Fig.…”

“…Plasma concentrations of YM466 were determined by HPLC following the report by Mano et al7 Briefly, 0.1 mL of YM‐59892 (5 μg/mL), an internal standard, and 1 mL of 50 mM phosphate buffer (pH 3.0) were added to 0.5 mL of plasma, and the mixture was applied onto an OASIS HLB solid‐phase extraction column (Waters, Milford, Massachusetts). After washing the column with 2 mL of 10% ethanol, 2 mL of ethanol was employed to elute YM466.…”

A liquid chromatographic–tandem mass spectrometric method for the determination of YM466, a novel Factor Xa inhibitor, in rat plasma

“…Although we have already established an HPLC-UV method [5], the present method using LC-MS/MS makes it possible to determine plasma concentrations 25 times lower. Furthermore, the pre-treatment procedures were much simplified and the analysis time was shortened, which resulted in greater efficiency.…”

“…In order to estimate the effective plasma concentration of YM466 in rats, a sensitive analytical method is necessary. Although, we have already established the bioanalytical method for YM466 in the plasma of rats and dogs using high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection [5], the lower limit of quantification (LOQ) using 1 ml of plasma was 10 ng/ml. This LOQ value may not be sufficient to determine pharmacologically effective plasma concentrations for YM466 in rats.…”

Absorption, distribution, metabolism and excretion of YM466, a novel factor Xa inhibitor, in rats

“…Plasma concentrations of YM466 were determined by an HPLC with ultraviolet detection method in which accuracy and precision have been validated [10]. In brief, to 1 ml of plasma, 0.1 ml of YM-59892 (5 mg/ml; internal standard) and 1 ml of 50 mm phosphate buffer were added, followed by loading onto an Oasis HLB solidphase extraction column (Waters, MA, USA), conditioned with 2 ml of methanol and 2 ml of water.…”