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On The Rate and Extent of Drug Delivery to the Brain
Open accessAbstract
To define and differentiate relevant aspects of blood-brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologically active drug molecule. Drug delivery to the brain can be comprehensively described using three parameters: Kp,uu (concentration ratio of unbound drug in brain to blood), CLin (permeability clearance into the brain), and Vu,brain (intra-brain distribution). The permeability of the blood-brain barrier is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a continuous (repeated) basis. Kp,uu can differ between CNS-active drugs by a factor of up to 150-fold. This range is much smaller than that for log BB ratios (Kp), which can differ by up to at least 2,000-fold, or for BBB permeabilities, which span an even larger range (up to at least 20,000-fold difference). Methods that measure the three parameters Kp,uu, CLin, and Vu,brain can give clinically valuable estimates of brain drug delivery in early drug discovery programmes.
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Cites
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Cited by
The blood-brain barrier: an engineering perspective
Wong, A. D., Ye, M., Levy, A. F., Rothstein, J. D., Bergles, D. E., & Searson, P. C. (2013) · Frontiers in Neuroengineering · doi:10.3389/fneng.2013.00007 · Cited by 662
Agrawal, M., Ajazuddin, Tripathi, D. K., Saraf, S., Saraf, S., Antimisiaris, S. G., Mourtas, S., Hammarlund-Udenaes, M., & Alexander, A. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.05.019 · Cited by 356
Self-citationFan, J., & de Lannoy, I. A. M. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.09.007 · Cited by 309
Wang, J., Hodes, G. E., Zhang, H., Zhang, S., Zhao, W., Golden, S. A., Bi, W., Menard, C., Kana, V., Leboeuf, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02794-5 · Cited by 274
Raub, T. J., Wishart, G. N., Kulanthaivel, P., Staton, B. A., Ajamie, R. T., Sawada, G. A., Gelbert, L. M., Shannon, H. E., Sanchez-Martinez, C., & De Dios, A. (2015) · Drug Metabolism and Disposition · doi:10.1124/dmd.114.062745 · Cited by 284
Metadata
- Authors
- Hammarlund-Udenaes, M., Fridén, M., Syvänen, S., & Gupta, A.
- Venue
- Pharmaceutical Research
- Published
- 2007-12-05
- Volume
- 25
- Issue
- 8
- Pages
- 1737-1750
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W2058780134
- Cited by
- 513
- References
- 4
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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