Evidence-based approach to assess passive diffusion and carrier-mediated drug transport

► Literature evidences do not support carrier-mediated only theory for cellular uptake. ► Passive diffusion and carrier-mediated processes coexisted for absorption. ► Cell membranes have higher molar ratio of lipids than proteins. ► Unknown transporter cannot explain all the drug transport phenomena. Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization.