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• W2022673067 abstract "The in situ brain perfusion technique was used to assess the impact of local capillary density, blood flow rate and P-gp-mediated efflux activity on regional drug exposure for the P-gp substrates colchicine, quinidine, verapamil, and loperamide, the perfusion flow rate marker diazepam, and the vascular volume marker inulin, in mdr1a(+/+) and mdr1a(−/−) mice. Regional perfusion flow rate varied 7.5-fold, and capillary density (based on vascular volume) varied 3.7-fold, across the 13 brain regions examined. The rate of regional flow, as well as P-gp-mediated colchicine efflux activity, was directly proportional to local capillary density. A decrease in perfusion rate attenuated verapamil brain uptake and had significant effect on P-gp-mediated efflux activity for this substrate in brain regions with lower capillary density. Regional brain uptake and calculated log D at pH 7.4 (clog D7.4) were well-related in P-gp-deficient mice, indicating that in the absence of P-gp-mediated efflux, physicochemical properties of the compound (i.e., lipophilicity) serve as the primary determinant of regional brain uptake. Loperamide regional brain uptake and P-gp effect during a 60-s brain perfusion or at 30 min after subcutaneous administration were significantly correlated with local capillary density. The highest P-gp-mediated efflux activity was consistently observed in cerebral cortex and midbrain regions for loperamide following short-term brain perfusion and at all time points following subcutaneous administration. These results in intact animal emphasize that the regionality of substrate exposure in brain as measured by the in situ brain perfusion technique is actually biologically relevant." @default.
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• W2022673067 date "2009-10-01" @default.
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• W2022673067 title "Regional differences in capillary density, perfusion rate, and P-glycoprotein activity: A quantitative analysis of regional drug exposure in the brain" @default.
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• W2022673067 doi "https://doi.org/10.1016/j.bcp.2009.06.001" @default.
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