QUANTIFICATION AND PHARMACOKINETICS OF BLOOD-BRAIN-BARRIER DISRUPTIONIN HUMANS

Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infus ion of mannitol into the cerebral arteries, has been used in the treat ment of brain tumors to increase drug delivery to tumor and adjacent b rain. However, the efficacy of HBBBD in brain tumor therapy has been c ontroversial. The goal of this study was to measure changes in vascula r permeability after HBBBD in patients with malignant brain tumors. Th e permeability (K-1) of tumor and normal brain blood vessels was measu red using rubidium-82 and positron emission tomography before and repe atedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K-1 in all patients. Baseline K-1 values were 2.1 +/- 1.4 and 34.1 +/- 22.1 mu l/minute/ml (+/- standard deviation) for brain and tumor, respectively. The peak absolute increases in K-1 following HBBBD were 20.8 +/- 11.7 and 19.7 +/- 10.7 mu l/minute/ml for brain and tumor, corresponding to percenta ge increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K-1 to near baseline for brain and tumor were 8.1 +/- 3.8 and 4.2 +/- 1.2 minutes, respectively. Simulati ons of the effects of HBBBD made using a very simple model with intraa rterial methotrexate, which is exemplary of drugs with low permeabilit y, indicate that 1) total exposure of the brain and tumor to methotrex ate, as measured by the methotrexate concentration-time integral (or a rea under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) expo sure tome at concentrations above 1 mu M, the minimal concentration re quired for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-train barrier disruption transiently increases delivery of water-soluble com pounds to normal brain and brain tumors. Most of the enhancement of ex posure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered withi n 5 to 10 minutes after disruption. However, the increased exposure an d exposure time that occur with methotrexate, the permeability of whic h is among the lowest of the agents currently used clinically, are lim ited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.