Assuming a drug is not injected intravenously, it will have to cross biological membranes in order to reach the blood from its initial site of application (within the gastrointestinal tract if oral or within a muscle or under the skin if intramuscular or subcutaneous etc). In the next sections, we review the mechanisms by which drugs may cross (or be prevented from crossing) membranes.

Passive diffusion

Much the commonest mechanism by which drugs cross biological membranes is passive diffusion. This is shown in below Figure. The drug is travelling left to right, beginning and ending in aqueous environments that are separated by a biological membrane. These membranes contain some proteins, but are primarily lipid in nature. The drug molecule starts (a) in the aqueous solution to the left of the membrane. There is no mechanism to direct the molecule to move in any specific direction; it simply wanders around randomly. At some point it happens to arrive at the interface between its current water environment and the lipid of the membrane. Here it may partition out of the aqueous phase into lipid solution within the membrane (b). It now continues its random wandering and may eventually reach the interface with the aqueous environment on the right, at which point it can partition back into aqueous solution (c).

Notice that the molecule effectively dissolves its way through the lipid membrane. The only driving force for movement is a concentration gradient. Given equal concentrations of drug on both sides of the membrane, there will be equal amounts of drug moving left-to-right and back again, with no net movement in either direction. Only when there is a higher concentration on the left hand side, will we see net movement as indicated in below Figure.


As the molecule has to spend some time in aqueous solution and some in the lipid phase, there are two requirements for this process to occur efficiently. It requires both:

– Aqueous solubility

– Lipid solubility

The commonest source of problems with passive diffusion is inadequate lipid solubility This generally arises with molecules that are polar (carry electrical charges) and are therefore readily water soluble, but cannot partition into the lipid phase of the membrane.


Drug companies generally prefer to develop potential drug molecules that are reasonably lipid soluble. Excessively water soluble ones may be incapable of absorption following oral administration and therefore need to be injected.


Facilitated diffusion and active transport

Where drugs undergo facilitated diffusion or active transport, there is a transporter protein that binds the drug molecule and carries it across the membrane. In this case the drug does not have to dissolve in the lipid membranes and there is no requirement for lipid solubility. This is shown in below Figure. With facilitated diffusion the carrier enables drug movement in either direction, but there is no active mechanism to pump drug in either direction. As with passive diffusion, net movement requires a concentration gradient to drive it. In contrast, active transport is an energy requiring, active process which pumps drug in a defined direction. In that case, net transport is possible under any circumstances, even occurring against a concentration gradient.


Figure: The mechanism of facilitated diffusion or active transport.


The transporter molecules that carry out facilitated diffusion and active transport are very selective; they will only bind to and transport, tightly defined groups of molecules. They have obviously arisen during evolution, to carry naturally occurring molecules across membranes. The vast majority of man-made drugs are chemically distinct from these natural substrates and consequently there are no carriers to which they can bind. Hence, the only mechanism by which most drugs can cross membranes is passive diffusion. Man-made drugs that are sufficiently similar to natural substrates and able to ‘hitch a ride’ on an existing carrier, include levodopa and gabapentin. These resemble the naturally occurring amino acids and can be carried by the Large neutral Amino acid Transporter (LAT1).