NSC 649890 is a flavone possessing anti-tyrosine kinase activity. It has shown potent growth inhibitory activity in a variety of in vitro and in vivo tumor models. The objectives of this project were to develop an analytical method for the assay of NSC 649890 in biological fluids, and to define its pharmacokinetics in vivo. An analytical method was developed employing HPLC with a phenyl column, a formate-buffered acetonitrile mobile phase, and UV detection at 264 nm. Murine pharmacokinetics was studied following bolus IV doses of 12.5, 25, 50, and 75 ~mol/kg. Pharmacokinetic profiles were biexponential with terminal half-lives between 180 and 230 minutes. Plasma concentrations were linear with respect to administered dose over the dose range of 12.5 to 50 ~mol/kg, but at doses above that level, higher plasma concentrations than would be predicted by linear kinetics were observed. Oral bioavailability following a single bolus intragastric dose of 25 fmol/kg in mice and 10 fmol/kg in dogs was 36 to 37%. Repeated daily intragastric doses resulted in decreased oral bioavailability in the mouse. Continuous intravascular infusion of 5-6 fmol/kg/day in dogs for 1-3 days produced steady-state plasma concentrations of 200-300 nM. These levels are in excess of those demonstrated to effectively inhibit the growth of various human tumor cell lines in in vitro assays. This dosing schedule was associated with severe gastrointestinal toxicity after approximately 60 hours of infusion. Canine pharmacokinetics was studied following IV doses of 25, 8 and 4 ~mol/kg. Severe gastrointestinal symptoms were observed at the higher 2 doses, and death of the dog at the highest dose. Four ~mol/kg was tolerated with mild softening of the stool and 1 of 2 dogs vomiting.
