The Critical Role of Passive Permeability in Designing Successful Drugs |
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Authors: | Dr. Li Di Prof. Per Artursson Dr. Alex Avdeef Prof. Leslie Z. Benet Prof. J. Brian Houston Dr. Manfred Kansy Edward H. Kerns Prof. Hans Lennernäs Dr. Dennis A. Smith Prof. Kiyohiko Sugano |
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Affiliation: | 1. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, CT 06340 USA;2. Department of Pharmacy, Uppsala University, 752 36 Uppsala, Sweden;3. in-ADME Research, 1732 First Avenue, #102, New York, NY 10128 USA;4. Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94143 USA;5. Division of Pharmacy & Optometry, Stopford Building, Oxford Road, Manchester, M13 9PT UK;6. Retired, Germany;7. Retired, USA;8. Retired, UK;9. College of Pharmaceutical Sciences, Department of Pharmacy, Ritsumeikan University, Noji-higashi, Kusatsu, Shiga, 525-8577 Japan |
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Abstract: | Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients. |
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Keywords: | passive permeability absorption P-gp metabolism blood-brain barrier renal clearance |
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