Efflux Transporters in the Brain

2007 ◽  
pp. 461-483
Author(s):  
H. Potschka ◽  
W. Löscher
Keyword(s):  
Efflux Transporters ◽  
The Brain

Effect of Neuroinflammation on ABC Transporters: Possible Contribution to Refractory Epilepsy

2018 ◽  
Vol 17 (10) ◽  
pp. 728-735 ◽  
Author(s):  
Xiaolin Deng ◽  
Yangmei Xie ◽  
Yinghui Chen
Keyword(s):  
Antiepileptic Drugs ◽  
Abc Transporters ◽  
Refractory Epilepsy ◽  
Vascular Endothelial Cells ◽  
Efflux Transporters ◽  
Vascular Endothelial ◽  
Intracellular Signalling Pathways ◽  
The Brain ◽  
Transporter Expression

Background & Objective: Epilepsy is a common and serious chronic neurological disorder that is mainly treated with antiepileptic drugs. Although current antiepileptic drugs used in clinical practice have advanced to the third generation, approximately one-third of patients are refractory to these treatments. More efficacious treatments for refractory epilepsy are therefore needed. A better understanding of the mechanism underlying refractory epilepsy is likely to facilitate the development of a more effective therapy. The abnormal expression and/or dysfunction of efflux transporters, particularly ABC transporters, might contribute to certain cases of refractory epilepsy. Inflammation in the brain has recently been shown to regulate the expression and/or function of ABC transporters in the cerebral vascular endothelial cells and glia of the blood-brain barrier by activating intracellular signalling pathways. Conclusion: Therefore, in this review, we will briefly summarize recent research advances regarding the possible role of neuroinflammation in regulating ABC transporter expression in epilepsy.

scholarly journals How to Explain Multidrug Resistance in Epilepsy?

2005 ◽  
Vol 5 (3) ◽  
pp. 107-112 ◽  
Author(s):  
Wolfgang Löscher
Keyword(s):  
Drug Targets ◽  
Initial Response ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Causative Mechanism ◽  
The Brain ◽  
Antiepileptic Drug Therapy

Despite advancements in antiepileptic therapy, about one third of people with epilepsy will remain intractable to medication. The initial response to antiepileptic drug therapy is highly predictive of long-term outcome. However, the mechanisms of medical intractability of epilepsy are only incompletely understood. Current interest is focused on two hypotheses: overexpression of drug efflux transporters and alterations in drug targets in the brain, with the most relevant causative mechanism(s) still to be elucidated.

scholarly journals SCIDOT-14. ENHANCING BRAIN RETENTION OF A KIF11 INHIBITOR SIGNIFICANTLY IMPROVES ITS EFFICACY IN A MOUSE MODEL OF GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi274-vi274
Author(s):  
Gautham Gampa ◽  
Rajappa Kenchappa ◽  
Afroz Mohammad ◽  
Karen Parrish ◽  
Minjee Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Blood Brain ◽  
Clinical Investigations ◽  
Molecule Inhibitor ◽  
Cellular Components ◽  
The Brain

Abstract Glioblastoma, the most common and lethal of brain tumors, is both highly invasive and proliferative. This allows tumor cells to infiltrate into regions of the brain with an intact blood brain barrier and be protected from effective therapeutics. Thus, an ideal glioblastoma therapy needs to target cellular components that drive both invasion and proliferation, with inhibitors that penetrate the blood brain barrier. The mitotic kinesin KIF11 meets these criteria and it can be targeted with ispinesib, a highly specific small molecule inhibitor. However, to be effective, ispinesib needs to cross the blood brain barrier and be retained within brain long enough to target glioblastoma cells when they are vulnerable, during mitosis.. We have examined the factors that affect distribution of ispinesib to both brain and glioblastoma. We find that delivery of ispinesib is limited by P-gp and Bcrp-mediated drug efflux at the blood brain barrier. Consequently, ispinesib levels are significantly lower in the infiltrative tumor margin relative to the tumor core, where the blood brain barrier is defective. We also show that elacridar—an inhibitor of the P-gp and Brcp efflux transporters—enhances delivery of ispinesib, and that co-administration of ispinesib with elacridar markedly slows tumor proliferation and prolongs survival in a mouse model of this disease. These results demonstrate the feasibility and efficacy of combining a potentially ideal therapeutic with a compound that enhances brain retention of this therapeutic, and provides support for utilizing this approach in clinical investigations of KIF11 inhibitors in GBM.

scholarly journals Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood–Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 595 ◽  
Author(s):  
Cui ◽  
Lotz ◽  
Rapp ◽  
Klinder ◽  
Himstedt ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Partition Coefficient ◽  
Blood Brain Barrier ◽  
New Method ◽  
Brain Barrier ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
The Brain

Movement of xenobiotic substances across the blood–brain barrier (BBB) is tightly regulated by various transporter proteins, especially the efflux transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). Avoiding drug efflux at the BBB is a unique challenge for the development of new central nervous system (CNS) drugs. Drug efflux at the BBB is described by the partition coefficient of unbound drug between brain and plasma (Kp,uu,brain) which is typically obtained from in vivo and often additionally in vitro measurements. Here, we describe a new method for the rapid estimation of the in vivo drug efflux at the BBB of rats: the measurement of the partition coefficient of a drug between brain and skeletal muscle (Kp,brain/muscle). Assuming a closely similar distribution of drugs into the brain and muscle and that the efflux transporters are only expressed in the brain, Kp,brain/muscle, similar to Kp,uu,brain, reflects the efflux at the BBB. The new method requires a single in vivo experiment. For 64 compounds from different research programs, we show the comparability to other approaches used to obtain Kp,uu,brain. P-gp- and BCRP-overexpressing cell systems are valuable in vitro tools for prescreening. Drug efflux at the BBB can be most accurately predicted based on a simple algorithm incorporating data from both in vitro assays. In conclusion, the combined use of our new in vivo method and the in vitro tools allows an efficient screening method in drug discovery with respect to efflux at the BBB.

scholarly journals Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain

2011 ◽  
Vol 13 ◽  
Author(s):  
Sagar Agarwal ◽  
Ramola Sane ◽  
Rajneet Oberoi ◽  
John R. Ohlfest ◽  
William F. Elmquist
Keyword(s):  
Drug Delivery ◽  
Glioblastoma Multiforme ◽  
Glioma Cells ◽  
Current Treatment ◽  
Efflux Transporters ◽  
Tumour Mass ◽  
Whole Brain ◽  
Active Efflux ◽  
Entire Brain ◽  
The Brain

Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood–brain barrier (BBB) restricts the delivery of many small and large molecules into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumour mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumour. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain–tumour-cell barrier (a barrier due to expression of efflux transporters in tumour cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumour and the invasive glioma cells.

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