An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (<i>N</i>-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016): TABLE 1

Polli, Joseph W.; Olson, Katie L; Chism, John P.; John-Williams, Lisa A St.; Yeager, Russ L.; Woodard, Sesha M.; Otto, Vicky R; Castellino, Stephen; Demby, Victoria E

doi:10.1124/dmd.108.024646

Cited by 231 publications

(227 citation statements)

References 14 publications

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“…Similar results as for dasatinib on the dominant role of P-gp at the BBB were found for the TKIs imatinib and lapatinib, which are good substrates for both P-gp and ABCG2 (6,34). Deficiency of Abcg2 alone did not lead to an increased brain accumulation, whereas single P-gp knockout mice had higher brain levels than WT mice.…”

Section: Discussionsupporting

confidence: 70%

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

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

168

123

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Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. We studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, we orally administered sorafenib to wild-type, Abcb1a/1b −/− , Abcg2 −/− , and Abcb1a/1b;Abcg2 −/− mice, completely lacking functional Abcb1a/1b, Abcg2, or both, respectively, and we studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2 −/− mice and 9.3-fold increased in Abcb1a/1b;Abcg2 −/− mice. Moreover, when wildtype mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that observed for Abcb1a/1b;Abcg2 −/− mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, that is, ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clinically, our findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319-26. ©2010 AACR.

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Section: Discussionsupporting

confidence: 70%

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

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

168

123

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“…These results showed no effect of abcg2 2/2 , a marked increase in brain exposure in abcb1a/b 2/2 , and an even greater increase in the triple knockout. The ability of P-gp and bcrp to work together to limit brain disposition has also been described for lapatinib and dasatinib (Chen et al, 2009;Polli et al, 2009). The results of Poller et al (2011) suggested that the mouse mdr1 limits the brain distribution of axitinib, with the role of bcrp being unclear.…”

Section: Transporters For Axitinibmentioning

confidence: 99%

In Vitro Characterization of Axitinib Interactions with Human Efflux and Hepatic Uptake Transporters: Implications for Disposition and Drug Interactions

Reyner¹,

Sevidal

West

et al. 2013

Drug Metab Dispos

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Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1, 2, and 3. The ATP-binding cassette (ABC) and solute carrier (SLC) transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ‡ 6 3 10 26 cm/s).Active efflux was observed in Caco-2 cells, and further evaluation in multidrug resistance gene 1 (MDR1) or breast cancer resistance protein (BCRP) transfected Madin-Darby canine kidney cells type 2 (MDCK) cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not BCRP. Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC 50 values of 3 mM and 4.4 mM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified because an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC 50 for each transporter. However, a GastroPlus simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 transfected human embryonic kidney 293 (HEK293) cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [ 14 C]axitinib-equivalents showed rapid absorption and distribution to all tissues except the brain. This suggests that efflux transport of axitinib may occur at the mouse blood-brain barrier.

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“…In particular, the drug efflux transporters expressed at the BBB play a very important role in limiting the brain penetration of a wide variety of compounds including frequently used chemotherapeutics and novel targeted agents. Two well-established drug efflux transporters, ABCB1 (P-glycoprotein, P-gp, MDR1) and ABCG2 (Breast Cancer Resistance Protein, BCRP), are abundantly expressed in the human and murine BBB and restrict most newly developed kinase inhibitors such as erlotinib, lapatinib, and palbociclib (15)(16)(17). As a consequence, the usefulness of such agents in glioblastoma treatment might be attenuated by an inadequate brain penetration.…”

Section: Introductionmentioning

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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Cited by 231 publications

References 14 publications

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

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

In Vitro Characterization of Axitinib Interactions with Human Efflux and Hepatic Uptake Transporters: Implications for Disposition and Drug Interactions

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

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