Flavopiridol, NSC 649890, is a flavone possessing anti-tyrosine kinase activity. Potent growth inhibitory activity in a variety of in vitro and in vivo tumor models has been demonstrated. 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, a formate-buffered acetonitrile mobile.phase, and UV detection at 264 nm. Murine pharmacokinetics was studied following bolus i.v. doses of 12.5, 25, 50, and 75 mu 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 mu mol/kg. However, at doses above 50 mu mol/kg, higher plasma concentrations than predicted by linear kinetics were observed. Bolus intragastric (IG) administration of 200 mu mol/kg to mice resulted in rapid adsorption, and peak plasma levels of approximately 8 mu M after 15 minutes followed by a rapid decline to approximately 0.8 mu M by 12 hours. This concentration is in the range of concentrations which are expected to produce 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 i.v. doses of 25, 8 and 4 mu mol/kg. Severe gastrointestinal symptoms were observed at the higher 2 doses, and death of the dog at the highest dose. Four mu mol/kg were tolerated with mild softening of the stool and 1 of 2 dogs vomiting. During initial INDA-directed toxicology studies, beagle dogs were given doses of 1.75 or 2.6 mg/kg/day by 24 or 72 hour continuous IV infusion. At the high dose, steady-state plasma concentrations of approximately 90 ng/ml were achieved, while at the low dose, steady-state concentrations were approximately 65 ng/ml. Total body clearances were from 1.3 to 1.4 l/hr/kg. Subsequent canine toxicology studies were conducted at a dose level of 1.5 mg/kg/day by continuous IV infusion for 72 hours. Steady-state plasma concentrations in these studies ranged from 23 to 34 ng/ml.
