Kinetic analysis of the role of plasma protein binding on brain drug uptake: effect of site specific binding and flow
| dc.contributor.committeeChair | Smith, Quentin R. | |
| dc.contributor.committeeMember | Srivenugopal, Kalkunte | |
| dc.contributor.committeeMember | Klein, Jochen | |
| dc.contributor.committeeMember | Weis, Margaret | |
| dc.contributor.committeeMember | Allen, David D. | |
| dc.creator | Mandula, Haritha | |
| dc.date.accessioned | 2016-11-14T23:15:38Z | |
| dc.date.available | 2011-02-18T20:17:30Z | |
| dc.date.available | 2016-11-14T23:15:38Z | |
| dc.date.issued | 2005-12 | |
| dc.degree.department | TTUHSC -- Pharmaceutical Sciences | en_US |
| dc.description.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. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/2346/13438 | en_US |
| dc.language.iso | eng | |
| dc.publisher | Texas Tech University | en_US |
| dc.rights.availability | Unrestricted. | |
| dc.subject | Plasma protein binding | en_US |
| dc.subject | Blood-brain barrier | en_US |
| dc.title | Kinetic analysis of the role of plasma protein binding on brain drug uptake: effect of site specific binding and flow | |
| dc.type | Dissertation |