Impact of transporters and enzymes from blood–cerebrospinal fluid barrier and brain parenchyma on CNS drug uptake

Wang, Qianwen; Zuo, Zhong

doi:10.1080/17425255.2018.1513493

Cited by 26 publications

(17 citation statements)

References 122 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These DMETs are involved in drug metabolisms and the uptake and efflux of a variety of drugs across the BBB, hence affecting drug distribution in the brain [42,43]. Brain drug distribution is associated with the efficacy and side effects of drugs for the treatment of many diseases, such as brain tumors, HIV-1 infection, and psychiatric disorders [44]. Therefore, obtaining DMET protein expression profiles at the BBB will provide more insights into the role of the BBB in regulating the pharmacological effects of central nervous system medications; and the information will also aid in drug development and the optimization of pharmacotherapy.…”

Section: Dmet Proteins Expressed At the Human Bbbmentioning

confidence: 99%

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-Based Proteomics of Drug-Metabolizing Enzymes and Transporters

Zhu

2020

Molecules

View full text Add to dashboard Cite

Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics is a powerful tool for identifying and quantifying proteins in biological samples, outperforming conventional antibody-based methods in many aspects. LC-MS/MS-based proteomics studies have revealed the protein abundances of many drug-metabolizing enzymes and transporters (DMETs) in tissues relevant to drug metabolism and disposition. Previous studies have consistently demonstrated marked interindividual variability in DMET protein expression, suggesting that varied DMET function is an important contributing factor for interindividual variability in pharmacokinetics (PK) and pharmacodynamics (PD) of medications. Moreover, differential DMET expression profiles were observed across different species and in vitro models. Therefore, caution must be exercised when extrapolating animal and in vitro DMET proteomics findings to humans. In recent years, DMET proteomics has been increasingly utilized for the development of physiologically based pharmacokinetic models, and DMET proteins have also been proposed as biomarkers for prediction of the PK and PD of the corresponding substrate drugs. In sum, despite the existence of many challenges in the analytical technology and data analysis methods of LC-MS/MS-based proteomics, DMET proteomics holds great potential to advance our understanding of PK behavior at the individual level and to optimize treatment regimens via the DMET protein biomarker-guided precision pharmacotherapy.

show abstract

Section: Dmet Proteins Expressed At the Human Bbbmentioning

confidence: 99%

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-Based Proteomics of Drug-Metabolizing Enzymes and Transporters

Zhu

2020

Molecules

View full text Add to dashboard Cite

show abstract

“…The transporters mediate not only the BBB passage of essential nutrients such as glucose, amino acids, and vitamins, but also the influx and efflux of the CNS drugs to and out of the brain (Table I), thereby influencing the concentration of drugs at the target site within the brain. Importantly, the transporters, which are expressed at the membrane of brain parenchymal cells, mediate the intracellular distribution of drugs within the brain, while transporters, expressed at the BBB, and BCSFB, influence elimination of the therapeutics (48,49).…”

Section: Carrier-mediated Transport (Cmt)mentioning

confidence: 99%

“…In contrast, V u,brain greater than 0.8 mL/g brain demonstrates the predominant distribution to the brain parenchymal cells. As the transporter-utilizing (pro)drugs and nanocarriers are distributed in and out of the brain parenchymal cells via transporters expressed at cellular membranes, the ISF concentration of the unbound (pro)drug or nanocarriers is not necessarily equal to that in the brain parenchymal cells (49). Moreover, the distribution to the brain parenchymal cells can be cell-specific depending on the expression of the particular transporter at the membrane of the individual cell.…”

Section: Intra-brain Distributionmentioning

confidence: 99%

Targeting Transporters for Drug Delivery to the Brain: Can We Do Better?

2022

View full text Add to dashboard Cite

Limited drug delivery to the brain is one of the major reasons for high failure rates of central nervous system (CNS) drug candidates. The blood–brain barrier (BBB) with its tight junctions, membrane transporters, receptors and metabolizing enzymes is a main player in drug delivery to the brain, restricting the entrance of the drugs and other xenobiotics. Current knowledge about the uptake transporters expressed at the BBB and brain parenchymal cells has been used for delivery of CNS drugs to the brain via targeting transporters. Although many transporter-utilizing (pro)drugs and nanocarriers have been developed to improve the uptake of drugs to the brain, their success rate of translation from preclinical development to humans is negligible. In the present review, we provide a systematic summary of the current progress in development of transporter-utilizing (pro)drugs and nanocarriers for delivery of drugs to the brain. In addition, we applied CNS pharmacokinetic concepts for evaluation of the limitations and gaps in investigation of the developed transporter-utilizing (pro)drugs and nanocarriers. Finally, we give recommendations for a rational development of transporter-utilizing drug delivery systems targeting the brain based on CNS pharmacokinetic principles.

show abstract

“…The transport of molecules is selectively regulated by proteins specifically expressed at the luminal and/or basolateral membranes of the epithelial cells, including ABC and SLC [17,19]. The BCSFB also expresses diverse metabolizing enzymes that inactivate endogenous and exogenous molecules, such as CYPs450, GSTs, and UGTs [29,30]. Additionally, the epithelial cells present infoldings on the basolateral membrane and microvilli on the apical membrane, increasing the transfer surface area to improve fluid secretion [31].…”

Section: The Blood-cerebrospinal Fluid Barriermentioning

confidence: 99%

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

et al. 2019

View full text Add to dashboard Cite

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.

show abstract

Impact of transporters and enzymes from blood–cerebrospinal fluid barrier and brain parenchyma on CNS drug uptake

Cited by 26 publications

References 122 publications

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-Based Proteomics of Drug-Metabolizing Enzymes and Transporters

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-Based Proteomics of Drug-Metabolizing Enzymes and Transporters

Targeting Transporters for Drug Delivery to the Brain: Can We Do Better?

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

Contact Info

Product

Resources

About