Coexistence of passive and carrier-mediated processes in drug transport

Abstract

The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a drug. Although it is often accepted that many drug substances are transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the majority of membrane drug transport processes in biological systems. Based on evidence of the physicochemical characteristics and of in vitro and in vivo findings for marketed drugs, as well as results from real-life discovery and development projects, we present the view that both passive transcellular processes and carrier-mediated processes coexist and contribute to drug transport activities across biological membranes.

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…However, for the involvement of apical efflux transporters, it may not be necessary to determine Pdif,AB if PAB is high enough to allow complete oral absorption, although using this rationale one must be confident that apical influx transporters are not responsible for the high PAB. Other methods for separating Pcar from Pdif,AB have been reviewed by Sugano et al [205] To our knowledge, the efflux ratio determined in Caco-2 cells is the only reported parameter used for the overall assessment of substrate properties of a particular drug substance for intestinal membrane transporters. The use of the efflux ratio as an initial screen for transporter effects is reasonable from a safety point of view considering the sensitivity of this parameter (transporter effects are counted twice as described earlier) that may account for some of the above mentioned elements that may influence the efflux ratio.…”

A biophysical model of intracellular distribution and perinuclear accumulation of particulate matter

“…The uptake of extracellular material across the plasma membrane of eukaryotic cells is well described and characterized by a variety of mechanisms going from the passive diffusion to the active transport [1]. The former, defined as a concentration gradient-driven mass transport of a compound, is considered the dominant route [1].…”

“…The former, defined as a concentration gradient-driven mass transport of a compound, is considered the dominant route [1]. The latter, including the endocytosis mediated processes, is in charge of taking up larger molecules and molecular complexes.…”

A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

“…Even a high‐quality dataset is influenced by the state of knowledge at the time of curation. This can explain part of the 20 false negatives, as a given molecule could be considered as absorbed passively just because its active transporter remains to be discovered15 (structures depicted in Figure S6).…”