Regulation of ABC Transporters Blood–Brain Barrier

Miller, David S.

doi:10.1016/bs.acr.2014.10.002

Cited by 131 publications

(72 citation statements)

References 68 publications

(84 reference statements)

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“…Multiple ATP-binding cassette (ABC) proteins are expressed on the luminal, blood-facing endothelial plasma membrane of the BBB, which restricts the permeability of large number of toxins including therapeutic agents (Miller, 2015). ABC transporters are ATP-driven efflux pumps for xenobiotics and endogenous metabolites.…”

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

Establishment and Dysfunction of the Blood-Brain Barrier

Zhao

Nelson

Betsholtz³

et al. 2015

Cell

1,241

1,128

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Structural and functional brain connectivity, synaptic activity and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit and intact blood-brain barrier (BBB) functions. Here, we examine the mechanisms regulating the formation and maintenance of the BBB and functions of BBB-associated cell types. Furthermore, we discuss the growing evidence associating BBB breakdown with the pathogenesis of inherited monogenic neurological disorders and complex multifactorial diseases including Alzheimer’s disease.

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Section: Cellular Components Of the Bbbmentioning

confidence: 99%

Establishment and Dysfunction of the Blood-Brain Barrier

Zhao

Nelson

Betsholtz³

et al. 2015

Cell

1,241

1,128

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“…The development of PET imaging approaches in humans has raised new opportunities to study P-gp function in situations in which this transporter may be overexpressed (36). Current protocols focusing on influx hindrance require partial P-gp inhibition to achieve substantial 11 C-verapamil baseline K 1 (34,38).…”

Section: Discussionmentioning

confidence: 99%

“…Modulation of P-gp function at the BBB, due to genetic polymorphism (35), environmental factors (36), or drug-drug interactions (37), may contribute to interindividual variability of brain exposure and subsequent pharmacodynamic response to CNS drugs, including pharmacoresistance (36). K 1 is estimated in the early distribution phase, where P-gp works against the concentration gradient between the plasma and the brain (12).…”

Section: Discussionmentioning

confidence: 99%

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Pottier¹,

Marie²,

Goutal³

et al. 2015

J Nucl Med

105

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The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used 11 C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. Methods: 11 C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. 11 C-metoclopramide brain kinetics were compared using PET in rats (n 5 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The 11 C-metoclopramide brain distribution (V T based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis. Results: 11 C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline 11 C-metoclopramide brain kinetics (V T 5 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm −3 using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose 11 C-metoclopramide V T (7.80 ± 1.43 mL⋅cm −3 ) with a 4.4-fold increase in K 1 (influx rate constant) and a 2.3-fold increase in binding potential (k 3 /k 4 ) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (V T 5 6.28 ± 0.48 mL⋅cm −3 ) with a 2.0-fold increase in K 1 and a 2.2-fold decrease in k 2 (efflux rate), with no significant impact on binding potential. In this situation, only parent 11 C-metoclopramide could be detected in the brains of P-gp-inhibited rats. Conclusion: 11 C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.

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“…It is known that there are several signaling pathways implicated in the cellular regulation of P-gp and BCRP at the BBB. 36 Thus, even though naloxone is a selective antagonist of the m-opioid receptors, the absence of Pgp and Bcrp upregulation in brain microvessels following the naloxone-precipitated opioid withdrawal may be explained by its effect on other non-opioid receptors, 37,38 which may also be involved in the regulation of these ABC transporters following a morphine chronic treatment. For example, naloxone showed to have a low-affinity for the NMDA receptor in a Xenopus oocytes model.…”

mentioning

confidence: 98%