No abstract

YM155 monobromide is a novel small-molecule survivin suppressant. The pharmacokinetics, distribution and excretion of YM155/[14C]YM155 were investigated using males and pregnant or lactating female rats after a single intravenous bolus administration. For the 0.1, 0.3 and 1 mg/kg YM155 doses given to male rats, increases in area under the plasma concentration-time curves were approximately proportional to the increase in the dose level. After administering [14C]YM155, radioactivity concentrations in the kidney and liver were highest among the tissues in both male and pregnant rats: e.g. 14.8- and 5.24-fold, respectively, and higher than in plasma at 0.1 h after dosing to male rats. The YM155 concentrations in the brain were lowest: 25-fold lower than in plasma. The transfer of radioactivity into fetuses was low (about 2-fold lower than in plasma). In lactating rats, the radioactivity was transferred into milk at a level 8- to 21-fold higher than for plasma. Radioactivity was primarily excreted in feces (64.0%) and urine (35.2%). The fecal excretion was considered to have occurred mainly by biliary excretion and partly by secretion across the gastrointestinal membrane from the blood to the lumen.

This paper describes a sensitive and selective liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for determination of the novel survivin suppressant YM155, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium, which is developed for the treatment of solid tumors. This method uses a liquid-liquid extraction from 0.25 mL of dog plasma. LC separation was carried out on a Genesis Silica column (50 mm x 3.0 mm i.d.) at a flow-rate of 0.5 mL/min. Compounds were eluted using a mobile phase of 5 mm ammonium acetate and 0.1% formic acid in water-0.1% formic acid in acetonitrile, 17:83 (v/v). MS/MS detection was carried out with an MDS-Sciex API3000 triple quadrupole mass spectrometer in positive electrospray ionization mode. The standard curve was linear from 0.05 to 50 ng/mL (r > or = 0.9968). The lower limit of quantitation was 0.05 ng/mL. Good intra- and inter-day assay precision (within 7.4% RSD) and accuracy (within +/-12.3%) were obtained. The extraction recovery was 66.2%. The method was successfully applied to preclinical pharmacokinetic studies in dogs.