A.5 Transfer through membranes
Substances are transported through membranes by osmosis, filtration, passive
diffusion, facilitated diffusion, active transport, endocytosis and exocytosis.
Passive diffusionis the major route for the transport of drugs across membranes.
It occurs down a concentration gradient from a high to a low concentration. In
passive diffusion the drug dissolves into the lipid membrane from the aqueous
medium, diffuses across the membrane and dissolves out of the membrane into
the aqueous medium. Since the interiors of membranes are nonpolar, passive
diffusion is most effective for uncharged nonpolar species. Charged and highly
polar species are not easily transported through a membrane by passive diffu-
sion. However, a potential drug must have sufficient polar character to pene-
trate the hydrophilic surface of the membrane. Consequently, the structures of
potential drugs must contain a balanced ratio of lipid solubilizing regions to
water solubilizing regions if a sufficient concentration of the compound is to
cross a membrane by passive diffusion.
Active transport is also an important route for the transfer of drugs through a
membrane by a so calledcarrier protein. The solute combines with a specific
protein in the membrane, causing this protein to change its conformation. This
change results in the transport of the solute from one side of the membrane to the
other, where it is released into the aqueous medium. The rate of active transport is
dependenton the concentration of the solute at the absorption sites. It follows first
order kinetics at concentrations less than those required to saturate the available
carriers but changes to zero order at concentrations above the saturation point.
Consequently, increasing a drug’s concentration above the saturation limit in the
extracellular fluid does not increase the rate at which the drug is delivered to its
active site. Active transport usually operates from a low concentration to a high
concentration, which requires the cell to expend large quantities of energy.
Carrier proteins are highly selective, transporting solutes with specific chemical
structures. As they are normally involved in the transport of many naturally
occurring compounds they will often transport drugs with structures related to
these natural products. This type of structural relationship can be use in the
approach to the design of new drugs.
Facilated diffusion also involves the use of a carrier protein. It differs from
active transport in that it occurs from a high to a low concentration and so does
not require energy to be supplied by the cell. However, falicilated diffusion
appears to play a minor role in the transport of drugs through membranes.
APPENDIX 5 TRANSFER THROUGH MEMBRANES 249