New approaches to in vitro models of blood–brain barrier drug transport

Terasaki, Tetsuya; Ohtsuki, Sumio; Hori, Satoko; Takanaga, Hitomi; Nakashima, Emi; Hosoya, Ken

doi:10.1016/s1359-6446(03)02858-7

Cited by 157 publications

(96 citation statements)

References 73 publications

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“…Also, tight junction protein such as claudine-5 and occludin are also expressed in these cells . Further, the BBB permeability clearances of several compounds estimated in TR-BBB cells appear quite similar to in vivo evaluations (Terasaki et al, 2003). TR-BBB cells have already been used to demonstrate that transporters such as taurine transporter (TauT), system A isoform (ATA2) are expressed in rat brain endothelium (Kang et al, 2002;Takanaga et al, 2002).…”

Section: Discussionmentioning

confidence: 73%

The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

Lee¹,

Kang²

2010

Biomolecules and Therapeutics

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-The blood-brain barrier (BBB) transport of acetylcholinesterase (AChE) inhibitors, donepezil and tacrine suggested to be mediated by choline transport system in our previous study. Therefore, in the present study, we investigated the interaction of other AChE inhibitors, rivastigmine and galantamine with choline transporter at the BBB. The effects of rivastigmine and galantamine on the transport of choline by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB cells) were characterized by cellular uptake study using radiolabeled choline. The uptake of [

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Section: Discussionmentioning

confidence: 73%

The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

Lee¹,

Kang²

2010

Biomolecules and Therapeutics

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“…To date, several cell culture systems have been established as in vitro BBB model (Terasaki et al, 2003). Given the localized expression of P-gp, primary cultured brain microvessel endothelial cells have been widely used for the investigation of P-gp-mediated transport across BBB (Loscher and Potschka, 2005).…”

Section: Discussionmentioning

confidence: 99%

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Zhu

Wang

Markowitz

et al. 2006

Neuropsychopharmacol

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Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentrationdependent manner. The IC 50 values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 mM, respectively, whereas the IC 50 values of PALI were 4100 mM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood-brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1-50 mM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC 50 value of 5.87 mM. Following exposure to 10 mM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB.

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“…76,[81][82][83][84][85] The essential features of in vitro models of the BBB is that they reproduce key features of the intact BBB and, most importantly, that a positive result in such a model effectively predicts brain penetration in vivo. The model must therefore have both good construct validity and good predictive validity.…”

Section: In Vitro Assessment Of Brain Penetrationmentioning

confidence: 99%

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

et al. 2005

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Summary:The worldwide market for therapies for CNS disorders is worth more than $50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer's disease, stroke, and Parkinson's disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12-16 years) compared with a non-CNS drug (10 -12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders.

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New approaches to in vitro models of blood–brain barrier drug transport

Cited by 157 publications

References 73 publications

The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

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