The Effect of Breast Cancer Resistance Protein and P-Glycoprotein on the Brain Penetration of Flavopiridol, Imatinib Mesylate (Gleevec), Prazosin, and 2-Methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic Acid (PF-407288) in Mice

Abstract

ABSTRACT:The role of breast cancer resistance protein (Bcrp) and the combined activities of Bcrp and P-glycoprotein (P-gp, Mdr1a/1b) in limiting the brain penetration of drugs at the blood-brain barrier (BBB) were investigated using wild-type FVB, Mdr1a/1b(؊/؊), (؊/؊), Bcrp(؊/؊), and Mdr1a/1b(؊/؊), (؊/؊)Bcrp(؊/؊) mice. Four drugs, flavopiridol, imatinib mesylate (Gleevec), PF-407288, and prazosin, with different transport specificity for BCRP/Bcrp and MDR1/ Mdr1a were selected, and the drug levels in plasma, cerebrospinal fluid, and brain of mice were determined. Flavopiridol and prazosin were identified as substrates for both mouse Bcrp and Mdr1a with greater transport associated with Bcrp. The brain/plasma (B/P) ratios at 0.5 and 2 h in Mdr1a/1b(؊/؊), (؊/؊) and Bcrp(؊/؊) mice were 1-to 2-fold for both compounds, whereas the ratios in Mdr1a/1b(؊/؊), (؊/؊)Bcrp(؊/؊) mice were more than 5-fold of those observed in FVB mice. For imatinib, a better substrate of P-gp than Bcrp, the B/P ratios in Bcrp(؊/؊) were comparable to those in FVB mice, whereas the B/P ratios in Mdr1a/1b(؊/؊), (؊/؊) and Mdr1a/1b(؊/؊), (؊/؊)Bcrp(؊/؊) mice were more than 4-and 28-fold of those in FVB mice at both time points, respectively. Finally, the Bcrp-specific substrate PF-407288 exhibited comparable B/P ratios in Mdr1a/1b(؊/؊), (؊/؊) and Bcrp(؊/؊) mice and slightly but significantly increased B/P ratios in Mdr1a/ 1b(؊/؊), (؊/؊)Bcrp(؊/؊) mice compared with those in FVB mice. The B/P ratios of compounds in Mdr1a/1b(؊/؊), (؊/؊)Bcrp(؊/؊) mice compared with those in Mdr1a/1b(؊/؊), (؊/؊) mice clearly demonstrate that Bcrp impairs the brain penetration of its substrates. Moreover, P-gp and Bcrp at BBB function synergistically to limit the brain penetration of shared substrates.It is widely recognized that the tight junctions between adjacent brain endothelial cells forming the blood-brain barrier (BBB) restrict the entry of compounds by paracellular diffusion from the blood to the brain. Moreover, the transcellular diffusion of compounds through the brain endothelial cells can also be impeded by transmembrane efflux transporters, such as P-glycoprotein (P-gp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). These efflux transporters can eliminate xenobiotics from the brain against a concentration gradient, thereby limiting central nervous system (CNS) exposure to these compounds. Indeed, the prominent effect of P-gp at the BBB is well established, and P-gp is functionally important in limiting the brain penetration of its substrates (Schinkel et al., 1994;Chen et al., 2003;Scherrmann, 2005). Like P-gp, BCRP is another major member of the ATP-binding cassette family of drug transporters and is highly expressed in the BBB as well. BCRP has been found at the luminal side of human brain capillary endothelial cells (Cooray et al., 2002), and the mRNA level of mouse analog Bcrp was ϳ700 times greater in brain microvessels than in the cortex of the mice (Cisternino et al., 2004), implying that mouse Bcrp may play a key role at the BBB. B...

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

“…Again, Abcb1a/1b;Abcg2 −/− mice had the highest imatinib and lapatinib brain concentrations. And finally, Zhou et al (35) reported a study in which they tried to gain insight into the role of ABCG2 at the BBB. In that study, more than 1,000 compounds were screened in vitro for their affinity for P-gp and ABCG2 to find a substrate with good affinity for ABCG2/Abcg2 and negligible affinity for P-gp.…”

P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

“…They can thus confer multidrug resistance and limit the oral absorption and brain penetration of many clinically used anticancer drugs (15)(16)(17)(18)(19), which may well limit their therapeutic efficacy, especially against brain metastases. It is therefore important to know whether everolimus interacts with these transporters.…”

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

“…Cripe et al [34] reported that the in vivo inhibition of P-gp by zosuquidar might lead to the activation of non-Pgp transmembrane proteins, such as BCRP. In addition, BCRP and P-gp presumably work in synergy or in a compensatory manner to restrict the passage of their concerted substrates into the CNS in mice, and P-gp can compensate for the deletion of BCRP, as suggested by Zhou et al [33] . In addition, zosuquidar can be considered to be an inducer of P-gp or a dual P-gp/BCRP inducer in brain capillaries.…”

“…This may be associated with that prazosin or zosuquidar in combined use altere the response to the modulation of other transmembrane protein. Also, it has been reported that BCRP and P-gp work in synergy or in a compensatory manner for the efflux of their substrates and the modulation of a transmembrame protein by the inducer/inhibitor alteres the efflux effect of other transmembrane protein [33,34] .…”

“…The inhibition of BCRP by prazosin may cause the activation of P-gp in the brain capillaries of mice. A compensatory relationship has been reported to exist between P-gp and BCRP, and P-gp has also been reported to be more prominent and inducible than BCRP at the BBB [33,34] Prazosin has been indicated to be only an inducer of P-gp [23][24][25][26][27] . In addition, many BCRP and P-gp substrates and modulators overlap [13,27,35] .…”