The Critical Role of Passive Permeability in Designing Successful Drugs

Di, LiPharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, USA (författare)

This paper is dedicated to the memory of our gifted colleague, Dr. Konstantin Tsinman, who recently passed away due to COVID19. Dr. Tsinman contributed greatly to improve our ability to measure passive permeability and solubility in high‐throughput format. He will be truly missed in the field.
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.

Artursson, PerUppsala universitet,Institutionen för farmaci(Swepub:uu)perartur (författare)
Avdeef, Alexin-ADME Research, USA (författare)
Benet, Leslie Z.Department of Bioengineering and Therapeutic Sciences, UCSF, USA (författare)
Houston, J. BrianDivision of Pharmacy & Optometry, Stopford Building, UK (författare)
Kansy, ManfredRetired, Germany (författare)
Kerns, Edward H.Retired, USA (författare)
Lennernäs, HansUppsala universitet,Institutionen för farmaci(Swepub:uu)hanslenn (författare)
Smith, Dennis A.Retired, UK (författare)
Sugano, KiyohikoCollege of Pharmaceutical Sciences, Department of Pharmacy, Ritsumeikan University, Japan (författare)
Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, USAInstitutionen för farmaci (creator_code:org_t)

Av författaren/redakt...: Di, Li; Artursson, Per; Avdeef, Alex; Benet, Leslie Z.; Houston, J. Bria ...; Kansy, Manfred; visa fler...; Kerns, Edward H.; Lennernäs, Hans; Smith, Dennis A.; Sugano, Kiyohiko; visa färre...

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