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

doi:10.1016/j.tips.2005.11.009

Trends in Pharmacological Sciences

Volume 27, Issue 1, January 2006, Pages 17-24

https://doi.org/10.1016/j.tips.2005.11.009 Get rights and content

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.

Section snippets

Role of drug transporters in the pharmacology of anticancer drugs

The treatment of tumors with chemotherapeutic agents can be hampered by the development of drug resistance, a low and/or highly variable oral uptake of drugs and low tissue distribution of drugs. This can be caused by active drug efflux mediated by several members of the ATP binding cassette (ABC) superfamily of membrane transporters (designated ABCA to ABCG) [1].

The first of the ABC drug transporters discovered was the 170-kDa P-glycoprotein [ABCB1 (previously known as MDR1)]. Expression of

Breast cancer resistance protein: general aspects

BCRP was first cloned in 1998 based on its overexpression in a highly doxorubicin-resistant MCF7 breast cancer cell line (MCF-7/AdrVp) [28]. BCRP is as an ATP-dependent drug efflux transporter, and was initially shown to confer resistance to mitoxantrone, doxorubicin, daunorubicin and topotecan 28, 29. Because the gene was first isolated from a breast cancer cell line, it was called the breast cancer resistance protein (BCRP) gene. BCRP cDNA sequences were also cloned by two other research

Development of P-glycoprotein and BCRP inhibitors

First-generation inhibitors of P-glycoprotein were drugs (e.g. verapamil and cyclosporin A) that were already used in the clinic and were themselves transported by P-glycoprotein, suggesting that they act as competitive inhibitors. However, these first-generation inhibitors were difficult to apply in the clinic because: (i) their low binding affinities necessitated the use of high doses, resulting in unacceptable toxicity of the inhibitor; and (ii) pharmacokinetic interactions occurred as a

Pharmacological effects of P-glycoprotein and BCRP inhibitors: oral bioavailability

Oral application of anticancer drugs is often limited because of their low and highly variable bioavailability via this route. This can be caused by the presence of P-glycoprotein in the gastrointestinal tract, as was first demonstrated for paclitaxel in a preclinical study showing an increase in the apparent oral bioavailability from 11% in control mice to 35% in Mdr1a^−/− mice [61]. Interestingly, the low oral bioavailability of P-glycoprotein substrates similar to paclitaxel and docetaxel can

Pharmacological effects of P-glycoprotein and BCRP inhibitors: brain penetration

Thus far, the treatment of primary or metastatic brain tumors with chemotherapy is limited because of a low distribution of anticancer agents into brain tissue. An important reason for this low efficacy is the efficient protection of the brain against drugs involving two drug-permeability barriers: (i) the blood–brain barrier; and (ii) the blood–cerebrospinal fluid (CSF) barrier. The blood–brain barrier is formed primarily by the endothelium of the blood capillaries in the brain. The

Concluding remarks

During the past two decades, significant progress has been made in understanding the pharmacological and physiological role of ABC drug efflux transporters. Although these transporters were once thought to be of relevance only in making cancer cells resistant to anticancer drugs, it is now clear that they have a pronounced role in the pharmacokinetics (i.e. absorption, tissue distribution and hepatobiliary, intestinal and/or renal clearance) of a broad range of drugs, toxins, endogenous

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Trends in Pharmacological Sciences

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

Section snippets

Role of drug transporters in the pharmacology of anticancer drugs

Breast cancer resistance protein: general aspects

Development of P-glycoprotein and BCRP inhibitors

Pharmacological effects of P-glycoprotein and BCRP inhibitors: oral bioavailability

Pharmacological effects of P-glycoprotein and BCRP inhibitors: brain penetration

Concluding remarks

Biochim. Biophys. Acta

Cell

Trends Genet.

Adv. Drug Deliv. Rev.

Trends Pharmacol. Sci.

Adv. Drug Deliv. Rev.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Int. J. Pharm.

Bioorg. Med. Chem. Lett.

Cancer Lett.

Life Sci.

Eur. J. Cancer

Biochem. Biophys. Res. Commun.

Ann. Oncol.

Complete characterization of the human ABC gene family

J. Bioenerg. Biomembr.

Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues

Proc. Natl. Acad. Sci. U. S. A.

Absence of the Mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A

J. Clin. Invest.

Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient Mice

J. Natl. Cancer Inst.

Mammalian ABC transporters in health and disease

Annu. Rev. Biochem.

Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil

Cancer Res.

Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues

J. Histochem. Cytochem.

Coadministration of cyclosporin strongly enhances the oral bioavailability of docetaxel

J. Clin. Oncol.

Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer

J. Clin. Oncol.

P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs

J. Clin. Invest.

Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein

Clin. Cancer Res.

A family of drug transporters: the multidrug resistance-associated proteins

J. Natl. Cancer Inst.

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

Oncogene

The MRP family of drug efflux pumps

Oncogene

The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation

Curr. Drug Metab.

Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood–cerebrospinal fluid barrier

J. Clin. Invest.

Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity

J. Pharmacol. Exp. Ther.

Mrp4 confers resistance to topotecan and protects the brain from chemotherapy

Mol. Cell. Biol.

Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood-brain barrier

Cancer Res.

The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-gp inhibitors to enable the brain penetration of imatinib in patients

Cancer Res.

A multidrug resistance transporter from human MCF-7 breast cancer cells

Proc. Natl. Acad. Sci. U. S. A.

Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line

Cancer Res.

Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes

Cancer Res.

A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance

Cancer Res.