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

Tang, Seng Chuan; Sparidans, Rolf W.; Cheung, Ka Lei; Fukami, Tatsuki; Durmuş, Selvi; Wagenaar, Els; Yokoi, Tsuyoshi; Vlijmen, Bart J.M. van; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1158/1078-0432.ccr-13-1759

Cited by 32 publications

(42 citation statements)

References 41 publications

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“…Recently, Tang et al reported that carboxylesterase 1c (Ces 1c) was highly upregulated in Abcb1a/1b and/or Abcg2 knockout mice, and the plasma Ces 1c could tightly bind to everolimus inducing higher plasma stabilization and retention. 33 A similar phenomenon also appears to occur in this study with EPZ005687 and EPZ-6438 as plasma concentrations in knockout mice were about 20-fold higher than in WT mice, whereas the liver, kidney, heart and lung concentrations in wild-type and knockout mice were quite comparable. This indicates that some factor(s) affect the blood-to-tissue relationship of EPZ005687 and EPZ-6438 in knockout mice compared to WT mice.…”

Section: Discussionsupporting

confidence: 82%

ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2‐Inhibitors

Zhang

Gooijer

Buil

et al. 2015

Intl Journal of Cancer

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Enhancer of Zeste Homolog 2 (EZH2) has emerged as a promising therapeutic target for treatment of a broad spectrum of tumors including gliomas. We explored the interactions of five novel, structurally similar EZH2 inhibitors (EPZ005687, EPZ-6438, UNC1999, GSK343 and GSK126) with P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2). The compounds were screened by in vitro transwell assays and EPZ005687, EPZ-6438 and GSK126 were further tested in vivo using wild-type (WT), Abcb1 and/or Abcg2 knockout mice. All EZH2 inhibitors are transported by P-gp and BCRP, although in vitro the transporter affinity of GSK126 was obscured by very low membrane permeability. Both P-gp and Bcrp1 restrict the brain penetration of EPZ005687 and GSK126, whereas the brain accumulation of EPZ-6438 is limited by P-gp only and efflux of EPZ-6438 was completely abrogated by elacridar. Intriguingly, an unknown factor present in all knockout mouse strains causes EPZ005687 and EPZ-6438 retention in plasma relative to WT mice, a phenomenon not seen with GSK126. In WT mice, the GSK126 tissue-to-plasma ratio for all tissues is lower than for EPZ005687 or EPZ-6438. Moreover, the oral bioavailability of GSK126 is only 0.2% in WT mice, which increases to 14.4% in Abcb1;Abcg2 knockout mice. These results are likely due to poor membrane permeability and question the clinical usefulness of GSK126. Although all tested EZH2 inhibitors are substrates of P-gp and BCRP, restricting the brain penetration and potential utility for treatment of glioma, EPZ-6438 would be the most suitable candidate of this series.

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Section: Discussionsupporting

confidence: 82%

ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2‐Inhibitors

Zhang

Gooijer

Buil

et al. 2015

Intl Journal of Cancer

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“…The brain-to-plasma ratio is 0.04, which is close to the fraction of blood that is present in the brain vasculature and that will end up in the brain homogenate (39). Similarly, as shown before for the rapamycin analogue everolimus, the much higher levels of rapamycin in the plasma of the knockout strains is most likely due to the instability of rapamycin in plasma (31) and binding of rapamycin to carboxyl esterase 1c (Ces 1c), which protects rapamycin from degradation. Higher plasma levels in knockout mouse strains were also observed with AZD8055 and NVP-BEZ235, albeit that the effect size was much smaller.…”

Section: Discussionsupporting

confidence: 65%

“…1D). Recent work with rapamycin's analogue everolimus has demonstrated that carboxyl esterase 1c is more abundantly present in ABC-transporter knockout mice and responsible for enhanced stability in plasma (31). It is very likely that the higher blood level of rapamycin in knockout mice is similarly caused by avid binding of rapamycin to a serum factor, possibly Ces1c, which is more abundantly present in the plasma of knockout mice.…”

Section: Abcb1 Severely Impairs the Brain Penetration Of Rapamycinmentioning

confidence: 99%

PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

Lin

Gooijer

Hanekamp

et al. 2017

Clinical Cancer Research

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Purpose: The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma and offers several druggable targets. However, clinical efficacy of PI3K/mTOR inhibitors in glioblastoma has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against glioblastoma. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood-brain barrier (BBB) restricts the brain penetration of many drugs.Experimental Design: We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wild-type and ABC-transporter knockout mice. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models.Results: The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1, whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055, but not ZSTK474 or rapamycin. Concordantly, Abcb1a/bÀ/À mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold), and NVP-BEZ235 (4.5-fold), but not ZSTK474 relative to WT mice. Importantly, ABC transporters limited rapamycin brain penetration to subtherapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition.

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“…The brain disposition of another TKI, crizotinib, was substantially and similarly increased (14-fold) in Abcb1a/1b-and Abcb1a/1b;Abcg2-knockout mice, whereas no effect was observed of deletion of Abcg2 alone (Chuan et al, 2014). Similar results were found with the mammalian target of rapamycin (mTOR) inhibitor everolimus, where brain concentrations and brain-to-liver ratios were substantially increased in Abcb1a/1b-and Abcb1a/1b;Abcg2-knockout mice, but not in Abcg2-knockout mice (Tang et al, 2014).…”

Section: Drugs Only Affected By Abcb1a In Their Brain Accumulationsupporting

confidence: 61%

Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition

Durmuş

Hendrikx

Schinkel

2015

Advances in Cancer Research

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

Abstract: Purpose: To clarify the role of ABCB1, ABCG2, and CYP3A in blood and brain exposure of everolimus using knockout mouse models.Experimental Design: We used wild-type, Abcb1a/1b À/À , Abcg2 À/À , Abcb1a/1b;Abcg2

Cited by 32 publications

References 41 publications

ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2‐Inhibitors

ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2‐Inhibitors

PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition

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