Journal
PHARMACEUTICAL RESEARCH
Volume 31, Issue 8, Pages 2203-2219Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-014-1319-1
Keywords
blood-brain barrier; brain drug delivery; neuropharmacokinetics; neurotherapeutics; screening cascade; unbound-drug
Funding
- Janssen Pharmaceutica
Ask authors/readers for more resources
The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics. Forty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (K-p,K-uu,K-brain) and cell (K-p,K-uu,K-cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients. Assessment of K-p,K-uu,K-brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. K-p,K-uu,K-cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection. With the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available