Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs

P-glycoprotein (ABCB1) and breast cancer resistance protein [BCRP (also known as ABCG2)] are drug efflux transporters of the ATP binding cassette (ABC) family of proteins. Both P-glycoprotein and BCRP are located in the apical membrane of epithelial cells (e.g. in the intestinal wall and blood–brain...

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Bibliographic Details
Published in:Trends in pharmacological sciences (Regular ed.) 2006, Vol.27 (1), p.17-24
Main Authors: Breedveld, Pauline, Beijnen, Jos H., Schellens, Jan H.M.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacokinetics
Antiviral Agents - pharmacology
ATP Binding Cassette Transporter, Sub-Family G, Member 2
ATP-Binding Cassette Transporters - antagonists & inhibitors
ATP-Binding Cassette Transporters - physiology
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
Biological Availability
Brain - metabolism
Humans
Neoplasm Proteins - antagonists & inhibitors
Neoplasm Proteins - physiology
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Summary:P-glycoprotein (ABCB1) and breast cancer resistance protein [BCRP (also known as ABCG2)] are drug efflux transporters of the ATP binding cassette (ABC) family of proteins. Both P-glycoprotein and BCRP are located in the apical membrane of epithelial cells (e.g. in the intestinal wall and blood–brain barrier), where they can actively extrude a variety of structurally diverse drugs and drug metabolites. Consequently, the oral uptake and CNS penetration of substrate drugs can be low and variable. Inhibition of P-glycoprotein and/or BCRP is therefore a logical strategy to improve oral absorption, CNS penetration and delivery of anticancer agents to brain tumors or CNS metastases. As outlined in this review, this concept of improved oral pharmacokinetics has been demonstrated extensively for the anticancer drugs paclitaxel and topotecan both in preclinical models and in patients, and improved CNS penetration has been shown for paclitaxel, docetaxel and imatinib in preclinical models.
ISSN:0165-6147
1873-3735
DOI:10.1016/j.tips.2005.11.009