NSC 649890 is a flavone which is an inhibitor of protein tyrosine kinase. 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 mice and dogs. An analytical method was developed employing HPLC with a phenyl column, formate-buffered acetonitrile mobile phase, and UV detection at 264 nm. Murine pharmacokinetics was studied following bolus intravenous doses of 12.5, 25, 50, and 75 micromoles/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 micromoles/kg, but at doses above that level, higher plasma concentrations than would be predicted by linear kinetics were observed. Bolus intragastric (IG) administration of 200 micromoles/kg to mice resulted in rapid adsorption, and peak plasma levels of approximately 8 micromoles after 15 minutes followed by a rapid decline to approximately 0.8 micromoles by 12 hours. This concentration is in the range of concentrations which might be expected to have antitumor activity based on the results of in vitro studies. The oral bioavailability was approximately 23%. Mice dosed at this level showed severe diarrhea and lethargy by 8 to 10 hours following administration. Canine pharmacokinetics was studied following intravenous doses of 25, 8 and 4 micromoles/kg. Severe gastrointestinal symptoms were observed at the higher 2 doses, and death of the dog at the highest dose; 4 micromoles/kg was tolerated with mild softening of the stool and vomiting in 1 of 2 dogs.
