In Vitro–In Vivo Extrapolation of Key Transporter Activity at the Blood–Brain Barrier

Trapa, Patrick; Troutman, Matthew D.; Lau, Thomas Y. K.; Wager, Travis T.; Maurer, Tristan S.; Patel, Nandini; West, Mark; Umland, John P.; Carlo, Anthony; Feng, Bo; Liras, Jennifer

doi:10.1124/dmd.118.083279

Cited by 37 publications

(63 citation statements)

References 24 publications

(35 reference statements)

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“…Transporter proteomics has been used in the past decade to study expression in the BBB, but mostly from a perspective of drug exposure (Uchida et al, 2011a; Trapa et al, 2019), and many questions on the effect of aging and disease on efflux transporter expression and function are still open. The physiology and pathophysiology, as well as the cell biology and biochemistry of transport, are new fields.…”

Section: Discussionmentioning

confidence: 99%

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Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

Erdő

Krajcsi

2019

Front. Aging Neurosci.

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During the last decade, several articles have reported a relationship between advanced age and changes in the integrity of the blood-brain barrier (BBB). These changes were manifested not only in the morphology and structure of the cerebral microvessels but also in the expression and function of the transporter proteins in the luminal and basolateral surfaces of the capillary endothelial cells. Age-associated downregulation of the efflux pumps ATP-binding cassette transporters (ABC transporters) resulted in increased permeability and greater brain exposure to different xenobiotics and their possible toxicity. In age-related neurodegenerative pathologies like Alzheimer’s disease (AD), the amyloid-β (Aβ) clearance decreased due to P-glycoprotein (P-gp) dysfunction, leading to higher brain exposure. In stroke, however, an enhanced P-gp function was reported in the cerebral capillaries, making it even more difficult to perform effective neuroprotective therapy in the infarcted brain area. This mini-review article focuses on the efflux functions of the transporters and receptors of the BBB in age-related brain pathologies and also in healthy aging.

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Section: Discussionmentioning

confidence: 99%

“…One uncertainty is the correlation of expression and activity of efflux proteins. In general, it is assumed that protein expression and activity for ABCB1 and ABCG2 correlate (Uchida et al, 2011a; Trapa et al, 2019). However, it is not always the case when mRNA levels and function have been monitored (Vilas-Boas et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

Erdő

Krajcsi

2019

Front. Aging Neurosci.

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“…This information is critical when applying the species differences in proteomic transporter expression to scale Kp to human. 2,10 2 | MATERIAL S AND ME THODS…”

Section: Introductionmentioning

confidence: 99%

“…For example, in the MDCK-MDR1 test system,Figure 4A, illustrates that for efflux ratio less than 3, there is a minimal amount (<2-fold) of functional P-gp-mediated efflux in rats. This IVIVC can guide project teams on the potential impact of substrates with weak to moderate P-gp efflux when evaluating compounds for neuroscience projects 10. Similarly, for compounds that are solely restricted by BCRP, the IVIVC of BCRP-mediated efflux at the rodent BBB can be compared to the in vitro MDCK-BCRP cell line as inFigure 4B.…”

mentioning

confidence: 99%

Optimization of dose and route of administration of the P‐glycoprotein inhibitor, valspodar (PSC‐833) and the P‐glycoprotein and breast cancer resistance protein dual‐inhibitor, elacridar (GF120918) as dual infusion in rats

Rowbottom

Pietrasiewicz

Tuczewycz

et al. 2021

Pharmacology Res & Perspec

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Transporters can play a key role in the absorption, distribution, metabolism, and excretion of drugs. Understanding these contributions early in drug discovery allows for more accurate projection of the clinical pharmacokinetics. One method to assess the impact of transporters in vivo involves co‐dosing specific inhibitors. The objective of the present study was to optimize the dose and route of administration of a P‐glycoprotein (P‐gp) inhibitor, valspodar (PSC833), and a dual P‐gp/breast cancer resistance protein (BCRP) inhibitor, elacridar (GF120918), by assessing the transporters’ impact on brain penetration and absorption. A dual‐infusion strategy was implemented to allow for flexibility with dose formulation. The chemical inhibitor was dosed intravenously via the femoral artery, and a cassette of known substrates was infused via the jugular vein. Valspodar or elacridar was administered as 4.5‐hour constant infusions over a range of doses. To assess the degree of inhibition, the resulting ratios of brain and plasma concentrations, Kp's, of the known substrates were compared to the vehicle control. These data demonstrated that doses greater than 0.9 mg/hr/kg valspodar and 8.9 mg/hr/kg elacridar were sufficient to inhibit P‐gp‐ and BCRP‐mediated efflux at the blood‐brain barrier in rats without any tolerability issues. Confirmation of BBB restriction by efflux transporters in preclinical species allows for subsequent prediction in humans based upon the proteomic expression at rodent and human BBB. Overall, the approach can also be applied to inhibition of efflux at other tissues (gut absorption, liver clearance) or can be extended to other transporters of interest using alternate inhibitors.

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“…In in vitro to in vivo extrapolation (IVIVE), in vivo drug transport, or metabolism is predicted from data obtained in vitro, using correction parameters such as the relative expression factor (REF) and relative activity factors (RAF). This allows a reduction of the number of assays using animals, by employing data acquired with cultured cells [126,295,296].…”

Section: In Silico Modelsmentioning

confidence: 99%

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

et al. 2019

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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.

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In Vitro–In Vivo Extrapolation of Key Transporter Activity at the Blood–Brain Barrier

Cited by 37 publications

References 24 publications

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

Optimization of dose and route of administration of the P‐glycoprotein inhibitor, valspodar (PSC‐833) and the P‐glycoprotein and breast cancer resistance protein dual‐inhibitor, elacridar (GF120918) as dual infusion in rats

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

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