Does transbilayer diffusion have a role in membrane transport of drugs?

The existing consensus on coexistence of transbilayer diffusion and carrier-mediated transport as two main mechanisms for drugs crossing biological membranes was recently challenged by a systems biology group. Their transporters-only hypothesis is examined in this article using published experimental evidence. The main focus is on the key claim of their hypothesis, stating that ‘the drug molecules cross pure phospholipid bilayers through transient pores that cannot form in the bilayers of cell membranes, and thus transbilayer drug transport does not exist in cells’. The analysis shows that the prior consensus remains a valid scientific view of the membrane transport of drugs.

► The transporters-only hypothesis of membrane transport of drugs shows serious flaws. ► No published data support the proposed bilayer transport via transient aqueous pores. ► Drug molecules do not need pores to enter bilayer – accumulation is easy to observe. ► Tissue accumulation is caused by other mechanisms in addition to active transport. ► Transbilayer diffusion remains indispensable contribution to transport of many drugs.