title: 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.
abstract: 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 microns 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 microliters/g/min in the tumor. Influx rate constants in the cortex were 1.3-1.9 microliters/g/min and in the brain adjacent to tumor were 1.7-2.8 microliters/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 (micrograms/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.
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering, New York, New York 10021.
authors.forename: W R
authors.initials: WR
authors.lastname: Shapiro
authors.forename: R M
authors.initials: RM
authors.lastname: Voorhies
authors.forename: E M
authors.initials: EM
authors.lastname: Hiesiger
authors.forename: P B
authors.initials: PB
authors.lastname: Sher
authors.forename: G A
authors.initials: GA
authors.lastname: Basler
authors.forename: L E
authors.initials: LE
authors.lastname: Lipschutz
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000378:metabolism*; D002339:Carotid Arteries; D005910:Glioma / Q000378:metabolism*; D007269:Injections, Intra-Arterial; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D008727:Methotrexate