Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human

Warren, Mark S.; Zerangue, Noa; Woodford, Katie; Roberts, Lori M.; Tate, Emily H.; Feng, Bo; Li, Cheryl; Feuerstein, Thomas J.; Gibbs, John P.; Smith, Bill J.; Morais, Sonia M. de; Dower, William J.; Koller, Kerry J.

doi:10.1016/j.phrs.2009.02.007

Cited by 210 publications

(144 citation statements)

References 60 publications

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“…Although based on mRNA level, Mdr1a expression is slightly higher than that of Bcrp in mouse brain homogenate (Lee et al, 2005), Mdr1a expression could be much higher than that of Bcrp at the mouse BBB because Mdr1a is more enriched than Bcrp in BBB compared with brain homogenate (12-versus 5.6-fold) (Lee et al, 2005). Pfizer internal data have also confirmed that Mdr1a expression is higher than Bcrp expression at the mouse BBB (Warren et al, 2009). Consequently, the impact of functional impairment of Bcrp on the brain penetration of Bcrp and P-gp shared substrates probably becomes smaller than that predicted from the in vitro Bcrp transport activities.…”

Section: Function Of P-gp and Bcrp On The Cns Penetration Of Drugsmentioning

confidence: 91%

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

Zhou

Schmidt²,

Nelson³

et al. 2009

Drug Metab Dispos

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128

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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...

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Section: Function Of P-gp and Bcrp On The Cns Penetration Of Drugsmentioning

confidence: 91%

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

Zhou

Schmidt²,

Nelson³

et al. 2009

Drug Metab Dispos

Self Cite

128

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“…An understanding of the possible mechanisms behind this cooperation can be gained by looking at the relative expression of P-gp and BCRP (capacities of the two transporters) at the BBB, as well as the relative affinity for substrate drugs. Warren et al (2009) showed that the mRNA levels of P-gp in the brain vascular endothelial cells of mice was approximately 5-fold greater than the mRNA levels of BCRP. Likewise, Kamiie et al (2008) quantified membrane transporter levels using LC-MS and reported approximately 5-fold higher levels of P-gp at the mouse BBB compared with BCRP.…”

Section: Distribution Of Sorafenib To the Brain Is Limited By Bcrp 229mentioning

confidence: 99%

The Role of the Breast Cancer Resistance Protein (ABCG2) in the Distribution of Sorafenib to the Brain

Agarwal¹,

Sane²,

Ohlfest³

et al. 2010

J Pharmacol Exp Ther

146

137

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ATP-binding cassette transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been shown to work in concert to restrict brain penetration of several tyrosine kinase inhibitors. It has been reported that P-gp is dominant in limiting transport of many dual P-gp/BCRP substrates across the blood-brain barrier (BBB). This study investigated the influence of P-gp and BCRP on the central nervous system (CNS) penetration of sorafenib, a multitargeted tyrosine kinase inhibitor currently being evaluated in clinical trials for glioma. In vitro studies showed that BCRP has a high affinity for sorafenib. Sorafenib inhibited P-gp, but did not seem to be a P-gp substrate in vitro. CNS distribution studies showed that transport of sorafenib to the brain was restricted because of active efflux at the BBB. The brain-to-plasma equilibrium-distribution coefficient

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“…Exploring interspecies differences in those transporter that may be involved in drug efflux at the BBB, Warren et al (102) measured mRNA expression of the various ABC transporters (based upon quantitative PCR) in the brain and brain microvessel endothelia cells from human, rat, mouse, bovine, and pigs. Through this work, they identified 41 transporter genes in humans, 39 in rats, 38 in mouse, 21 in cattle, and 21 in swine.…”

Section: Blood-cns Partitioning: Passive Versus Active Transportmentioning

confidence: 99%

“…Through this work, they identified 41 transporter genes in humans, 39 in rats, 38 in mouse, 21 in cattle, and 21 in swine. These investigators concluded that interspecies differences in transporter expression could be an important consideration when selecting an animal model for CNS drug development (102).…”

Section: Blood-cns Partitioning: Passive Versus Active Transportmentioning

confidence: 99%

Factors Influencing the Use and Interpretation of Animal Models in the Development of Parenteral Drug Delivery Systems

Martinez

2011

AAPS J

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Abstract. Depending upon the drug and drug delivery platform, species-specific physiological differences can lead to errors in the interspecies extrapolation of drug performance. This manuscript provides an overview of the species-specific physiological variables that can influence the performance of parenteral dosage forms such as in situ forming delivery systems, nanoparticles, microspheres, liposomes, targeted delivery systems, lipophilic solutions, and aqueous suspensions. Also discussed are those factors that can influence the partitioning of therapeutic compounds into tumors, the central nervous system and the lymphatics. Understanding interspecies differences in the movement and absorption of molecules is important to the interpretation of data generated through the use of animal models when studying parenteral drug delivery.

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Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human

Cited by 210 publications

References 60 publications

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

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

The Role of the Breast Cancer Resistance Protein (ABCG2) in the Distribution of Sorafenib to the Brain

Factors Influencing the Use and Interpretation of Animal Models in the Development of Parenteral Drug Delivery Systems

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