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Investigation of the role of transpo...
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Park, Seonghee.
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Investigation of the role of transporters in the absorption and secretion of drugs across the blood-brain barrier.
紀錄類型:
書目-電子資源 : Monograph/item
正題名/作者:
Investigation of the role of transporters in the absorption and secretion of drugs across the blood-brain barrier./
作者:
Park, Seonghee.
面頁冊數:
110 p.
附註:
Source: Dissertation Abstracts International, Volume: 66-05, Section: B, page: 2537.
Contained By:
Dissertation Abstracts International66-05B.
標題:
Health Sciences, Pharmacy. -
電子資源:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3176210
ISBN:
9780542156762
Investigation of the role of transporters in the absorption and secretion of drugs across the blood-brain barrier.
Park, Seonghee.
Investigation of the role of transporters in the absorption and secretion of drugs across the blood-brain barrier.
- 110 p.
Source: Dissertation Abstracts International, Volume: 66-05, Section: B, page: 2537.
Thesis (Ph.D.)--Rutgers The State University of New Jersey - New Brunswick, 2005.
The overall objective of this dissertation was to advance the knowledge of mechanisms of drug transport to the brain. Cultures of bovine brain microvessel endothelial cells (BMECs) and a mouse brain perfusion technique were employed as in vitro and in vivo models of the blood-brain barrier (BBB), respectively. Two model compounds were studied: Biotin, a water soluble vitamin, to probe BBB influx pathway and saquinavir, a human immunodeficiency virus (HIV) protease inhibitor, to probe BBB efflux pathway. Transport mechanisms of biotin were characterized and the results of in vitro and in vivo studies were compared to assess how well the in vitro model was correlated to transport properties in vivo. Furthermore, the mechanisms responsible for the low brain uptake of saquinavir, were investigated to provide a better understanding of the role of efflux transporters at the BBB.
ISBN: 9780542156762Subjects--Topical Terms:
1017737
Health Sciences, Pharmacy.
Investigation of the role of transporters in the absorption and secretion of drugs across the blood-brain barrier.
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The overall objective of this dissertation was to advance the knowledge of mechanisms of drug transport to the brain. Cultures of bovine brain microvessel endothelial cells (BMECs) and a mouse brain perfusion technique were employed as in vitro and in vivo models of the blood-brain barrier (BBB), respectively. Two model compounds were studied: Biotin, a water soluble vitamin, to probe BBB influx pathway and saquinavir, a human immunodeficiency virus (HIV) protease inhibitor, to probe BBB efflux pathway. Transport mechanisms of biotin were characterized and the results of in vitro and in vivo studies were compared to assess how well the in vitro model was correlated to transport properties in vivo. Furthermore, the mechanisms responsible for the low brain uptake of saquinavir, were investigated to provide a better understanding of the role of efflux transporters at the BBB.
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Biotin was transported by saturable and Na+-dependent processes. Inhibition studies using various biotin derivatives and structural analogs suggested structural requirements for efficient substrate interactions with the transporter. Results of biotin uptake by the in vitro- and in vivo-BBB models showed a good agreement, suggesting that despite potential species differences, the kinetic parameters, functional properties, and effects of inhibitors were well preserved between BMECs and intact mice brains.
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In the second part, cellular efflux transporters such as P-glycoprotein (P-gp) and multidrug resistance associated proteins (Mrps) and their effects on saquinavir brain uptake were characterized. Mice brains were perfused with buffer containing saquinavir in the absence and presence of selective inhibitors of P-gp and Mrps. Inclusion of GF120918 (10 muM) and MK571 (100 muM) in the perfusate resulted in a more than 7-fold and 4.4-fold increase in the brain uptake of saquinavir, respectively. Neither GF120918 nor MK571 altered the integrity of the BBB during perfusion. While the current results reaffirm that saquinavir is a P-gp substrate, this is the first report implicating the Mrp transporter family in the limited brain uptake and retention of saquinavir in vivo in mice.
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Overall, the current results demonstrate that influx and efflux membrane transporters play important roles in xenobiotic absorption across the BBB.
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