عنوان

Characterization of Influx Transporters in the Blood-Brain Barrier:

شماره

TL1hb365p1

زبان متن نوشتاري يا گفتاري و مانند آن

انگلیسی

عنوان اصلي

Characterization of Influx Transporters in the Blood-Brain Barrier:

نام عام مواد

[Thesis]

نام نخستين پديدآور

Lin, Lawrence

عنوان اصلي به قلم نويسنده ديگر

Implications for Drug Delivery

نام ساير پديدآوران

Giacomini, Kathleen M

تاریخ نشرو بخش و غیره

2015

کسي که مدرک را اعطا کرده

Giacomini, Kathleen M

امتياز متن

2015

متن يادداشت

Membrane transport proteins of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies have been found to play essential roles in the absorption, distribution and elimination of drugs. However, much of the pharmacologic research on transporters has focused primarily on the intestine, liver and kidney. Here we focus on transporters in the blood-brain barrier (BBB), a complex barrier that limits penetration of most molecules from the blood into the brain. Research on transporters in the BBB has historically been centered on the ABC transporters that prevent drug entry into the brain, but recent advances suggest that SLC transporters may play an important role in mediating the uptake of many pharmacologic agents into the central nervous system (CNS). The goal of this dissertation research was to understand the role and function of several SLC transporters in the BBB, including the amino acid transporter LAT1, the organic cation transporter MATE1, the amine transporters OCT1, OCT3 and SERT, and the organic anion transporters OATP1A2 and OATP2B1. We performed inhibition and substrate screens using stably-transfected cell lines against a library of CNS-active drugs. We were able to identify four novel, structurally-diverse inhibitors of LAT1 and developed a rat perfusion model to test LAT1 substrates for in vivo relevance. For MATE1, we found that the majority of compounds tested from our library were inhibitors of MATE1, and identified 15 novel substrates, suggesting that MATE1 may be involved in the disposition of these drugs. Since organic anion transporting polypeptides are known to play a role in the influx of molecules into the brain, we performed substrate screens and identified 24 novel substrates of OATP1A2, most of which are cationic drugs. About one-third of the OATP1A2 substrates were also substrates of its rodent ortholog, rat Oatp2. Finally, we found that at high concentrations, metformin is able to inhibit the uptake of two CNS active monoamines, histamine and serotonin, by OCT1, OCT3 and SERT. Though further studies are clearly needed, we posit that reduced absorption of the two monoamines as a result of metformin's effects on OCT1, OCT3 and SERT may contribute to the gastrointestinal side effects associated with metformin use. The research presented here has important implications for CNS drug delivery, as our results have expanded the chemical space, particularly the known substrates, of several transporters expressed in the BBB.

مستند نام اشخاص تاييد نشده

Ko, Jesse Sun-Woo

مستند نام اشخاص تاييد نشده

Lin, Lawrence

مستند نام تنالگان تاييد نشده

UCSF

نام الکترونيکي

فرمت انتشار

p

نوع ماده

[Thesis]

کد کاربرگه

276903

سطح دسترسي

a

تكميل شده

Y