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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

George C. Cotzias Laboratory of Neuro-Oncology, Department of Neurology, Memorial Sloan-Kettering Cancer Center [W. R. S., R. M. V., E. M. H., P. B. S., G. A. B., L. E. L.] and Department of Neurology, Cornell University Medical College, New York, New York 10021 [W. R. S.]

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 x 50 x 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 K₁ 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 k₂ was approximated for each tissue but was less reliable than the K₁ values. The k₂ for tumor, brain adjacent to tumor, and cortex was always higher than the corresponding K₁. 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 x time) was also highest in the cortex after barrier disruption. The [¹⁴C]MTX concentration x time (µg/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 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.

¹ Supported by NIH Grants CA 18856 and CA 39208.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

³ Present address: Ochsner Clinic, New Orleans, LA 70121.

⁴ Present address: Department of Neurology, New York University School of Medicine, New York, NY 10116.

Received 2/25/87. Revised 7/29/87. Revised 10/21/87. Accepted 10/26/87.

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