| Title |
Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA
|
|---|---|
| Published in |
Investigational New Drugs, January 2013
|
| DOI | 10.1007/s10637-013-9923-1 |
| Pubmed ID | |
| Authors |
Serena Marchetti, Dick Pluim, Monique van Eijndhoven, Olaf van Tellingen, Roberto Mazzanti, Jos H. Beijnen, Jan H. M. Schellens |
| Abstract |
We explored whether barasertib (AZD1152), a selective Aurora B kinase inhibitor, is a substrate for P-glycoprotein (Pgp, MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in vitro. Cell survival, drug transport, and competition experiments with barasertib pro-drug and the more active form of the drug (barasertib-hQPA) were performed using MDCKII (wild type, MDR1, BCRP, and MRP2) and LLCPK (wild type and MDR1) cells and monolayers, and Sf9-BCRP membrane vesicles. Moreover we tested whether P-gp and BCRP affect the oral pharmacokinetics, tissue distribution, and myelotoxicity of barasertib in vivo using Bcrp1(-/-)/Mdr1a/1b (-/-) (triple knockout) and wild type mice. In cell survival experiments expression of BCRP and MDR1 resulted in significant resistance to barasertib. In transwell experiments, barasertib-hQPA was transported by BCRP and MDR1 efficiently. In Sf9-BCRP membrane vesicles, both barasertib and barasertib-hQPA significantly inhibited the BCRP-mediated transport of methotrexate. In contrast, no active transport of barasertib by MRP2 was observed, and overexpression of MRP2 did not affect cytotoxicity of barasertib. In vivo, systemic exposure as well as bioavailability, brain penetration, kidney and liver distribution and myelotoxicity of barasertib-hQPA were statistically significantly increased in Bcrp1(-/-)/Mdr1a/1b(-/-) compared with wild type mice (p<0.001). Barasertib is transported efficiently by P-gp and BCRP/Bcrp1 in vitro. In vivo, genetic deletion of P-gp and BCRP in mice significantly affected pharmacokinetics, tissue distribution and myelotoxicity of barasertib-hQPA. Possible clinical consequences for the observed affinity of barasertib for P-gp and BCRP need to be explored. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 20 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 2 | 10% |
| Unknown | 18 | 90% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 5 | 25% |
| Student > Ph. D. Student | 2 | 10% |
| Researcher | 2 | 10% |
| Student > Master | 2 | 10% |
| Librarian | 1 | 5% |
| Other | 0 | 0% |
| Unknown | 8 | 40% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 5 | 25% |
| Agricultural and Biological Sciences | 3 | 15% |
| Chemistry | 2 | 10% |
| Pharmacology, Toxicology and Pharmaceutical Science | 1 | 5% |
| Nursing and Health Professions | 1 | 5% |
| Other | 0 | 0% |
| Unknown | 8 | 40% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 29 January 2013.
All research outputs
#17,285,668
of 25,373,627 outputs
Outputs from Investigational New Drugs
#846
of 1,262 outputs
Outputs of similar age
#195,261
of 291,764 outputs
Outputs of similar age from Investigational New Drugs
#11
of 12 outputs
Altmetric has tracked 25,373,627 research outputs across all sources so far. This one is in the 21st percentile – i.e., 21% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,262 research outputs from this source. They receive a mean Attention Score of 4.9. This one is in the 27th percentile – i.e., 27% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 291,764 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 23rd percentile – i.e., 23% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 12 others from the same source and published within six weeks on either side of this one. This one is in the 8th percentile – i.e., 8% of its contemporaries scored the same or lower than it.