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Preclinical Experimental Therapeutics |
Northwestern University Institute for Neuroscience (M.V., E.W.-Y.K., Y.N., A.E., D.R.G.) and Department of Neurobiology and Physiology (M.V., E.W.-Y.K., D.R.G.), Northwestern University, Evanston, IL 60208; and Department of Neurology, Northwestern University Medical School, Evanston Northwestern Healthcare, Evanston, IL 60201 (M.J.A., C.V.A., D.R.G.); USA
2 Send correspondence to Dennis R. Groothuis, Department of Neurology, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA (drgroothuis{at}northwestern.edu).
Abstract
We compared tissue and plasma pharmacokinetics of 14C-sucrose in subcutaneous RG-2 rat gliomas after administration by 3 routes, intravenous bolus (IV-B; 50 µCi over 30 s), continuous IV infusion (IV-C, 50 µCi at a constant rate), and convection-enhanced delivery (CED, 5 µCi infused at a rate of 0.5 µl/min), and for 3 experimental durations, 0.5, 2, and 4 h. Plasma, tumor, and other tissue samples were obtained to measure tissue radioactivity. Plasma radioactivity in the CED group increased exponentially and lagged only slightly behind the IV-C group. After 90 min, plasma values were similar in all. Mean tumor radioactivity was 100 to 500 times higher in the CED group at each time point than in the IV-B and IV-C groups. Tumor radioactivity was homogeneous in the IV groups at 0.5 h and inhomogeneous at 1 and 2 h. In CED, radioactivity distribution was inhomogeneous at all 3 time points; highest concentrations were in tissue around tumor and in necrosis, while viable tumor contained the lowest and sometimes negligible amounts of isotope. Systemic tissue radioactivity values were similar in all groups. Efflux of 14C-sucrose from tumors was evaluated in intracerebral tumors (at 0.5, 1, 2, and 4 h) and subcutaneous tumors (at 0 to 0.5 h). Less than 5% of 14C activity remained in intracerebral tumors at each time point. The efflux half-time from the subcutaneous tumors was 7.3 ± 0.7 min. These results indicate rapid efflux of drug from brain tumor and marked heterogeneity of drug distribution within tumor after CED administration, both of which may be potentially limiting factors in drug delivery by this method.
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