Kinetic analysis of the role of plasma protein binding on brain drug uptake: Effect of site specific binding and flow

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Title: Kinetic analysis of the role of plasma protein binding on brain drug uptake: Effect of site specific binding and flow
Author: Mandula, Haritha
Abstract: Drug delivery to brain is complicated by multiple factors including low blood -brain barrier (BBB ) passive permeability , active BBB efflux transport , and plasma protein binding . The mechanism and quantitative contribution of plasma protein binding to brain drug uptake have been debated for >25 years . In most studies , measured brain drug uptake has exceeded that predicted by the in vitro serum free fraction (fu ) , leading to the hypothesis that an alteration occurs in the plasma protein as it passes through the capillary circulation producing enhanced disassociation and a marked increased in fu . Drugs bind to specific sites on plasma proteins with the primary contributors being Sudlow site I and II of albumin and the central binding site of á1 -acid glycoprotein (AAG ) . We tested the enhanced dissociation hypothesis using drugs that bind selectively to albumin Sudlow I , albumin Sudlow II , AAG and drugs that bind to more than one site . Brain uptake (Kin ) was measured in the absence and presence of plasma protein using the in situ rat brain perfusion technique . Drug fu in the arterial perfusate was measured by ultrafiltration and /or equilibrium dialysis . From the measured brain uptake , a BBB permeability -surface area (PSu ) was calculated . Brain uptake Kin for each tested drug agreed with that predicted using the Kety -Crone -Renkin equation [Kin = F (1 -e -fu x PSu /F )] from separate measurements of BBB PSu , fu and brain perfusion fluid flow (F ) . No statistically significant evidence was found for enhanced dissociation . In some experiments , drug uptake Kin was determined in the presence and absence of plasma protein at different F . For drugs with a BBB PSu /F < 1 .0 , brain uptake was independent of F and plasma protein binding was restrictive with a BBB Kin that varied directly with perfusate fu . In contrast , when PSu /F > 1 .0 , plasma protein binding was nonrestrictive on brain uptake so that the single -pass brain extraction exceeded fu . By decreasing F , a compound could be transitioned from restrictive to nonrestrictive . In summary , the results emphasize the importance of plasma protein binding in brain drug uptake and suggest that accurate predictions can be obtained using the modified Kety -Crone Renkin equation .
URI: http : / /hdl .handle .net /2346 /1264
Date: 2005-12

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Kinetic analysis of the role of plasma protein binding on brain drug uptake: Effect of site specific binding and flow. Doctoral dissertation, Texas Tech University. Available electronically from http : / /hdl .handle .net /2346 /1264 .

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