Drug distribution in the Body II

Membrane Permeation
An ability to penetrate lipid bilayers is a
prerequisite for the absorption of drugs,
their entry into cells or cellular organelles,
and passage across the bloodbrain
barrier. Due to their amphiphilic
nature, phospholipids form bilayers
possessing a hydrophilic surface and a
hydrophobic interior. Substances
may traverse this membrane in three
different ways.
Diffusion. Lipophilic substances
(red dots) may enter the membrane
from the extracellular space (area
shown in ochre), accumulate in the
membrane, and exit into the cytosol
(blue area). Direction and speed of permeation
depend on the relative concentrations
in the fluid phases and the
membrane. The steeper the gradient
(concentration difference), the more
drug will be diffusing per unit of time
(Fick’s Law). The lipid membrane represents
an almost insurmountable obstacle
for hydrophilic substances (blue triangles).
Transport . Some drugs may
penetrate membrane barriers with the
help of transport systems (carriers), irrespective
of their physicochemical
properties, especially lipophilicity. As a
prerequisite, the drug must have affinity
for the carrier (blue triangle matching
recess on “transport system”) and,
when bound to the latter, be capable of
being ferried across the membrane.
Membrane passage via transport mechanisms
is subject to competitive inhibition
by another substance possessing
similar affinity for the carrier. Substances
lacking in affinity (blue circles) are
not transported. Drugs utilize carriers
for physiological substances, e.g., L-dopa
uptake by L-amino acid carrier across
the blood-intestine and blood-brain
barriers, and uptake of aminoglycosides
by the carrier transporting
basic polypeptides through the luminal
membrane of kidney tubular cells
. Only drugs bearing sufficient resemblance
to the physiological substrate
of a carrier will exhibit affinity for it.
Finally, membrane penetration
may occur in the form of small membrane-
covered vesicles.