Pharmacokinetics of Tumor Cell Exposure to [14C]Methotrexate after Intracarotid Administration without and with Hyperosmotic Opening of the Blood-Brain and Blood-Tumor Barriers in Rat Brain Tumors: A Quantitative Autoradiographic Study1

Using quantitative autoradiography, we investigated the entry over 90 min of |l4C]methotrexate (MTX) into Q gliomas implanted bilaterally into Wistar rat brains. The [I4C]MTX was administered into the right carotid artery, yielding ipsilateral "arterial" brain and tumor concentra tions and contralateral "systemic'" concentrations. In a separate group of tumor-bearing rats, mannitol 1.6 M was given into the right carotid artery prior to administering the |I4C]MTX to disrupt the blood-brain barrier on the ipsilateral side. |"(']MT\ tissue concentrations were measured in regions of 50 x 50 x 20 urn in tumor, peritumoral brain tissue (brain adjacent to tumor), and cerebral cortex. In the nonmannitol experiments, tissue concentrations from the rats at each time interval were fitted using a nonlinear curve fitting program, and the pharmacokinetic values of influx and efflux of [I4C]MTX into the three compartments were calcu lated. The influx rate constant K¡for |14qMTX ranged from 1.3 to 8.2 fil/g/min in the tumor. Influx rate constants in the cortex were 1.3-1.9 fil/g/min and in the brain adjacent to tumor were 1.7-2.8 ¿tl/g/min. The efflux rate constant *2 was approximated for each tissue but was less reliable than the A",values. The ki for tumor, brain adjacent to tumor, and cortex was always higher than the corresponding K,. Peak |I4C]MTX concentrations in the tumor were highest after arterial infusion with hyperosmolar barrier disruption, lower after arterial administration with out barrier modification, and lowest after systemic administration. How ever, cortical |MC]MTX concentration was also highest after arterial administration with barrier modification and higher than the highest tumor concentration. Furthermore, tissue exposure (concentration x time) was also highest in the cortex after barrier disruption. The |I4QMTX concentration x time (/xg/min/g x 90 min ±SEM) ratio between tumor and cortex after systemic administration was 33.4 ± 4.1:15.7 ±1.9; after arterial administration it was 96.3 ±11.7:30.3 ± 3.1; after arterial administration with barrier disruption it was 266.6 ± 28.8:311.2 ±15.9. The greatest tumorcortex ratio (3.1:1) occurred with arterial drug administration without barrier disruption. Disrupting the barrier enough to permit increased tumor exposure actually increased cortical exposure to a greater degree. The resulting poorer therapeutic ratio would not appear to support this technique in humans, at least for neurotoxic drugs.