Mitigating permeability-mediated risks in drug discovery.
BACKGROUND
Adequate permeability is essential for good oral absorption and proper interpretation of pharmacokinetic and pharmacological data. Permeability-limiting absorption and distribution, however, are complex phenomena involving multiple mechanisms and organs ranging from gastro-intestine, liver, kidney to BBB, while the options for pharmaceutical improvement of permeability are quite limited.


METHODS
In this article, the comprehensive in silico, in vitro and in vivo/ex vivo/in situ tools to assess permeability are reviewed, alongside their advantages and limitations. Several key points relating to the in vivo predictive impact of in vitro permeability tools and the caveats when dealing with challenging discovery compounds were also addressed, using drug discovery cases and statistics in Novartis.


RESULTS
The integrated strategy to properly utilize existing permeability tools for mitigating the permeability-related absorption or safety risks at the different stages of drug discovery and development processes is presented.


CONCLUSIONS
It is critical to utilize the comprehensive in silico, in vitro and in vivo/ex vivo tools to dial out permeability issues in early drug discovery, ensuring the right questions to be addressed using the right tools at the right time.
Wang
Jianling
J
Novartis Institutes for Biomedical Research, Metabolism and Pharmacokinetics, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Jianling.wang@novartis.com
Skolnik
Suzanne
S
D000042:Absorption; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*
D004364:Pharmaceutical Preparations