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 Study

Using quantitative autoradiography, we investigated the entry over 90 min of [14C]methotrexate (MTX) into C6 gliomas implanted bilaterally into Wistar rat brains. The [14C]MTX was administered into the right carotid artery, yielding ipsilateral “arterial” brain and tumor concentrations 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 [14C]MTX to disrupt the blood-brain barrier on the ipsilateral side. [14C]MTX tissue concentrations were measured in regions of 50 × 50 × 20 µm 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 [14C]MTX into the three compartments were calculated. The influx rate constant K 1 for [14C]MTX ranged from 1.3 to 8.2 µl/g/min in the tumor. Influx rate constants in the cortex were 1.3–1.9 µl/g/min and in the brain adjacent to tumor were 1.7–2.8 µl/g/min. The efflux rate constant k 2 was approximated for each tissue but was less reliable than the K 1 values. The k 2 for tumor, brain adjacent to tumor, and cortex was always higher than the corresponding K 1. Peak [14C]MTX concentrations in the tumor were highest after arterial infusion with hyperosmolar barrier disruption, lower after arterial administration without barrier modification, and lowest after systemic administration. However, cortical [14C]MTX concentration was also highest after arterial administration with barrier modification and higher than the highest tumor concentration. Furthermore, tissue exposure (concentration × time) was also highest in the cortex after barrier disruption. The [14C]MTX concentration × time (µg/min/g × 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 tumor:cortex 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.