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Relevance of Breast Cancer Resistance Protein to Brain Distribution and Central Acting Drugs: A Pharmacokinetic Perspective

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Background: Breast Cancer Resistance Protein (BCRP, also known as ABCG2) is gaining momentum as a key transporter that restricts the permeability of a large number of therapeutic agents through the Blood-brain Barrier (BBB). BCRP is highly expressed in the apical membranes of epithelial cells of the small and large intestine, renal proximal tubules and canalicular membrane of hepatocytes, determining the gastrointestinal absorption and biodisposition of its substrates. It is also expressed in the luminal surface of endothelial cells of the BBB and Bloodspinal Cord Barrier (BSCB), where it undoubtedly limits the entry of a wide range of therapeutics into the CNS, potentially contributing to the therapeutic failure of CNS-acting drugs.

Methods: As the U.S. Food and Drug Administration and the European Medicines Agency recommend pre-clinical evaluation and clinical assessment of BCRP-mediated drug-drug interactions, compounds that are currently recognized as BCRP substrates, inhibitors or inducers will be addressed, focusing on their pharmacokinetic behaviour in plasma and brain.

Results: Recent studies indicated a strong BCRP expression in the microvasculature of the BBB in brain tumors, hypothesizing that this phenomenon critically influences the penetration of drugs in these tumors and potentially contributes to the failure of antitumor therapy. BCRP expression in brain tissue from patients or animal models of neurological and neurodegenerative diseases has also been investigated, and the role of BCRP and its implications for novel therapeutic interventions was also herein demonstrated.

Conclusions: The clinical significance of BCRP in drugs disposition is currently undeniable.
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Keywords: Breast cancer resistance protein; bioavailability; blood-brain barrier; cancer; multidrug resistance; neurodegenerative diseases; neurological disorders

Document Type: Review Article

Publication date: October 1, 2018

This article was made available online on July 19, 2018 as a Fast Track article with title: "Relevance of Breast Cancer Resistance Protein to Brain Distribution and Central Acting Drugs: A Pharmacokinetic Perspective".

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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