The membrane lipid bilayer is the most important barrier for drug
permeation since there are many lipid barriers
separating body compartments
Lipid: aqueous drug partition
coefficients describes the
ease with which a drug moves between aqueous and
lipid environments
Ionization
state of the drug is an important factor: charged
drugs diffuse-through lipid environments with
difficulty.
pH and the drug pKa,
important in determining the ionization
state, will influence significantly
transport (ratios of lipid-to
aqueous-soluble forms for weak acids and
bases described by the Henderson-Hasselbalch equation.
Uncharged
form: lipid-soluble
Charged
form: aqueous-soluble, not lipid
soluble; passes through
biological membranes with
difficulty
Electron Micrograph (left) and Lipid-Bilayer
Model (right)
Lipid-Bilayer with Membrane-Protein
courtesy of Professor Thomas M. Terry,
used with permission
Special Carriers
Peptides, amino acids, glucose are
examples of molecules then enter cells through
special carrier mechanisms.
Carriers:
active transport--energy
requiring
facilitated
diffusion--requires the carriers to
facilitate transport
saturable (unlike
passive diffusion, which is not saturable)
inhibitable
Transport that utilizes an ionic concentration
gradient to drive a co-transported molecule (same direction)
is classified as "symport"
Transport Systems
Although carrier-mediated processes are involved in
the excretion of certain drugs, most drugs do not require specific
transport mechanisms to enter the cell since they diffuse directly
through the lipid bilayer. Accordingly, the "lipid
solubility" of the drug as well as the magnitude of the
trans-membrane drug concentration are major factors that
determine drug pharmacokinetic behavior.
In the diagram above, the drug (transported molecule)
traverses the membrane by simple diffusion. Certain important
membrane proteins such as the nicotinic cholinergic receptor are
examples of proteins that are themselves ion channels. The
electric chemical gradient refers to the membrane potential, for
example -90 mv, which can serve as the driving force in "symport"
reactions.
Above figure courtesy of Professor Steve Wright and the
University of Arizona (c), used with permission
Endocytosis
Definition: Transport of solid matter or liquid into
the cell utilizing a coated vacuole or
vesicle.
Exocytosis
Definition: Transport of materials out of a cell
using a vesicle that first engulfs the
material and then is extruded through an
opening in the cell membrane.
Entry into cells by very
large substances (e.g., iron vitamin B12
-- each complexed with its binding protein --
movement across intestinal wall into the blood)
above to
begin
