Targeting anticancer drugs to the brain: II. 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 characterized in rats bearing the rat glioma-2 (RG-2) brain tumor. Following intraarterial administration of 3 mg/kg of OX, serial sacrifices were completed from 5 min to 5 hr after administration. Blood and tissue samples 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_maxbeing 40.6 μg/ml at 15 min after administration. OX concentrations in brain tumor were higher than in normal right and left brain hemispheres, and consistent with enhanced drug blood-tumor barrier (BTB) permeability seen in experimental models for brain tumors. Observed heart, liver, lung, and spleen OX concentrations were similar, ranging from approximately 2 μg/ml to 20 μg/ml. A unique technique was used to develop a global physiological pharmacokinetic model for OX. A hybrid or forcing function method was used to estimate individual tissue compartment biochemical parameters (i.e., partition and mass transfer coefficients). A log likelihood optimization scheme was used to determine the best model structure and parameter sets for each tissue. Most tissues required a 3-subcompartment structure to adequately describe the observed data. The global model was then reconstructed with an arterial blood and rest of body compartments that provided predicted OX concentrations in agreement with the data. The model development strategy provides a systematic approach to physiological pharmacokinetic model development.