TARGETING ANTICANCER DRUGS TO THE BRAIN .2. PHYSIOLOGICAL PHARMACOKINETIC MODEL OF OXANTRAZOLE FOLLOWING INTRAARTERIAL ADMINISTRATION TO RAT GLIOMA-2 (RG-2) BEARING RATS

The disposition of the anticancer drug oxantrazole (OX) was characteri zed in rats bearing the rat glioma-2 (RG-2) brain tumor. Following int raarterial administration of 3 mg/kg of OX, serial sacrifices were com pleted from 5 min to 5 hr after administration. Blood and tissue sampl es collected at the time of sacrifice were processed and measured for OX concentrations by HPLC The kidney had the greatest affinity for OX with the C(max) being 40.6 mug/ml at 15 min after administration. OX c oncentrations in brain tumor were higher than in normal right and left brain hemispheres, and consistent with enhanced drug blood-tumor barr ier (BTB) permeability seen in experimental models for brain tumors. O bserved heart, liver, lung, and spleen OX concentrations were similar, ranging from approximately 2 mug/ml to 20 mug/ml. A unique technique was used to develop a global physiological pharmacokinetic model for O X. A hybrid or forcing function method was used to estimate individual tissue compartment biochemical parameters (i.e., partition and mass t ransfer coefficients). A log likelihood optimization scheme was used t o determine the best model structure and parameter sets for each tissu e. Most tissues required a 3-subcompartment structure to adequately de scribe the observed data. The global model was then reconstructed with an arterial blood and rest of body compartments that provided predict ed OX concentrations in agreement with the data. The model development strategy provides a systematic approach to physiological pharmacokine tic model development.