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RG Blasberg, C Patlak and JD Fenstermacher
Ventriculocisternal perfusions with five isotopically labeled drugs were performed in the rhesus monkey and the resultant tissue diffusion concentration profiles in caudate nucleus were analyzed. The periventricular distribution space with respect to perfusate concentration was measured and expressed as microliters per 100 mg wet weight: hydroxyurea = 56; methotrexate = 27; thiotepa = 28; 1,3-bis(2- chloroethyl)-1-nitrosourea (BCNU) = 64 and cytosine arabinoside greater than 170. The apparent diffusion constants in caudate nucleus were determined for hydroxyurea and methotrexate (2.0 and 1.2 X 10(-6) cm2/sec, respectively); capillary permeability expressed as an extracellular space-transcapillary exchange half-time was estimated to be greater than 2 hours for both compounds. The extracellular fluid- transcapillary half-time was measured for thiotepa and BCNU (1.0 and 0.8 minute, respectively). Cytosine arabinoside continued to be concentrated by periventricular caudate nucleus during the course of perfusion; perfusate clearance measurements suggest a low capillary permeability. The apparent parenchymal diffusion constant and the capillary permeability of a drug in brain are discussed and are considered useful parameters for predicting drug levels after intrathecal administration.
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