| RRC ID |
63720
|
| Author |
Watanabe R, Esaki T, Ohashi R, Kuroda M, Kawashima H, Komura H, Natsume-Kitatani Y, Mizuguchi K.
|
| Title |
Development of an In Silico Prediction Model for P-glycoprotein Efflux Potential in Brain Capillary Endothelial Cells toward the Prediction of Brain Penetration.
|
| Journal |
J Med Chem
|
| Abstract |
Developing in silico models to predict the brain penetration of drugs remains a challenge owing to the intricate involvement of multiple transport systems in the blood brain barrier, and the necessity to consider a combination of multiple pharmacokinetic parameters. P-glycoprotein (P-gp) is one of the most important transporters affecting the brain penetration of drugs. Here, we developed an in silico prediction model for P-gp efflux potential in brain capillary endothelial cells (BCEC). Using the representative values of P-gp net efflux ratio in BCEC, we proposed a novel prediction system for brain-to-plasma concentration ratio (Kp,brain) and unbound brain-to-plasma concentration ratio (Kp,uu,brain) of P-gp substrates. We validated the proposed prediction system using newly acquired experimental brain penetration data of 28 P-gp substrates. Our system improved the predictive accuracy of brain penetration of drugs using only chemical structure information compared with that of previous studies.
|
| Volume |
64(5)
|
| Pages |
2725-2738
|
| Published |
2021-3-11
|
| DOI |
10.1021/acs.jmedchem.0c02011
|
| PMID |
33619967
|
| MeSH |
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Animals
Biological Transport / physiology*
Blood-Brain Barrier / metabolism*
Cell Line
Computer Simulation
Endothelial Cells / metabolism*
Gene Knockout Techniques
Humans
Organic Chemicals / metabolism*
Rats, Transgenic
|
| IF |
6.205
|
| Resource |
| Human and Animal Cells |
LLC(RCB0558)
LLC-GA5-CoL150(RCB0871) |
