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Mechanistic understanding of brain drug disposition to optimize the selection of potential neurotherapeutics in drug discovery

(2014) PHARMACEUTICAL RESEARCH. 31(8). p.2203-2219
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Abstract
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.
Keywords
neurotherapeutics, screening cascade, neuropharmacokinetics, brain drug delivery, blood-brain barrier, unbound-drug, CENTRAL-NERVOUS-SYSTEM, P-GLYCOPROTEIN, IN-VITRO, RECEPTOR OCCUPANCY, FREE FRACTION, CNS EXPOSURE, BINDING, DELIVERY, CSF, PHARMACODYNAMICS

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MLA
Loryan, Irena, et al. “Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery.” PHARMACEUTICAL RESEARCH, vol. 31, no. 8, 2014, pp. 2203–19, doi:10.1007/s11095-014-1319-1.
APA
Loryan, I., Sinha, V., Mackie, C., Van Peer, A., Drinkenburg, W., Vermeulen, A., … Hammarlund-Udenaes, M. (2014). Mechanistic understanding of brain drug disposition to optimize the selection of potential neurotherapeutics in drug discovery. PHARMACEUTICAL RESEARCH, 31(8), 2203–2219. https://doi.org/10.1007/s11095-014-1319-1
Chicago author-date
Loryan, Irena, Vikash Sinha, Claire Mackie, Achiel Van Peer, Wilhelmus Drinkenburg, An Vermeulen, Denise Morrison, Mario Monshouwer, Donald Heald, and Margareta Hammarlund-Udenaes. 2014. “Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery.” PHARMACEUTICAL RESEARCH 31 (8): 2203–19. https://doi.org/10.1007/s11095-014-1319-1.
Chicago author-date (all authors)
Loryan, Irena, Vikash Sinha, Claire Mackie, Achiel Van Peer, Wilhelmus Drinkenburg, An Vermeulen, Denise Morrison, Mario Monshouwer, Donald Heald, and Margareta Hammarlund-Udenaes. 2014. “Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery.” PHARMACEUTICAL RESEARCH 31 (8): 2203–2219. doi:10.1007/s11095-014-1319-1.
Vancouver
1.
Loryan I, Sinha V, Mackie C, Van Peer A, Drinkenburg W, Vermeulen A, et al. Mechanistic understanding of brain drug disposition to optimize the selection of potential neurotherapeutics in drug discovery. PHARMACEUTICAL RESEARCH. 2014;31(8):2203–19.
IEEE
[1]
I. Loryan et al., “Mechanistic understanding of brain drug disposition to optimize the selection of potential neurotherapeutics in drug discovery,” PHARMACEUTICAL RESEARCH, vol. 31, no. 8, pp. 2203–2219, 2014.
@article{5841660,
  abstract     = {{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.}},
  author       = {{Loryan, Irena and Sinha, Vikash and Mackie, Claire and Van Peer, Achiel and Drinkenburg, Wilhelmus and Vermeulen, An and Morrison, Denise and Monshouwer, Mario and Heald, Donald and Hammarlund-Udenaes, Margareta}},
  issn         = {{0724-8741}},
  journal      = {{PHARMACEUTICAL RESEARCH}},
  keywords     = {{neurotherapeutics,screening cascade,neuropharmacokinetics,brain drug delivery,blood-brain barrier,unbound-drug,CENTRAL-NERVOUS-SYSTEM,P-GLYCOPROTEIN,IN-VITRO,RECEPTOR OCCUPANCY,FREE FRACTION,CNS EXPOSURE,BINDING,DELIVERY,CSF,PHARMACODYNAMICS}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2203--2219}},
  title        = {{Mechanistic understanding of brain drug disposition to optimize the selection of potential neurotherapeutics in drug discovery}},
  url          = {{http://dx.doi.org/10.1007/s11095-014-1319-1}},
  volume       = {{31}},
  year         = {{2014}},
}

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