Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 2 CLINICAL PHARMACOKINETICS
Aqueous diffusion
Aqueous pores
Facilitated diffusion
Diffusion across membranes
HD
Drugs may cross membrane barriers by one of five
major mechanisms (Fig. 2.1):
● passive aqueous diffusion (especially via
aquaporins)
● passive lipid diffusion
● facilitated diffusion (including transport proteins
such as P-glycoprotein)
● pinocytosis
● active (energy-expending) transport.
The rate of transfer of a drug across a biological membrane
by passive diffusion (J) can be described by Fick’s
law of diffusion:
J = k(C 1 − C 2 ) where
k = D × A × P/T
Lipophilic molecules
Lipid membrane
H + + D – H + + D –
H + + D –
Lipid diffusion
Non-ionised
molecules
Ionised molecules
Pinocytosis
Fig. 2.1 Different ways in which drug molecules may
passively cross membranes. H, hydrogen; D, drug.
C 1 and C 2 denote the drug concentrations on each side
of the membrane and k is a proportionality constant
that incorporates the diffusion coefficient of the drug
(D), the thickness (T) and surface area (A) of the exposed
membrane and the partition coefficient (P) of the drug
product.
HD
HD
● D: the diffusion coefficient of the drug. Nonpolar
(nonionized) drugs are expected to diffuse quickly
through lipid and aqueous membranes.
● A: The surface area of the tissue exposed to the drug.
Transfer across membranes is usually faster in tissues
with a very large surface area (e.g. lung alveoli, small
intestinal villi) than across the membranes of organs
with a smaller surface area (e.g. stomach).
● T: The thickness of the membrane through which
drug transfer is occurring. The thicker the barrier,
the slower will be the rate of transfer.
● P: the partition coefficient describing the movement
of drug from the drug product into the biological
membrane.
● ∆C (i.e. C 1 − C 2 ): The concentration gradient is the
difference between the concentration of the drug on
either side of a membrane. This gradient is dependent
upon processes on both sides of the membrane,
e.g. the amount of drug administered (gradient
source) and the rate of removal from the contralateral
side of the membrane (gradient sink). If the drug
is removed very rapidly from the contralateral side
(e.g. because of high blood flow or rapid ionization
due to a different pH), the concentration gradient
will remain high and the rate of diffusion is expected
to be high.
While Fick’s law holds true for monolayers and can be
predictive for complex multilayer biological membranes,
transfer across biological membranes is highly complex
and deviations from Fick’s law point to the presence
of unaccounted factors influencing transmembrane
permeation.
Aqueous diffusion
Membranes have aqueous pores (protein channels
termed aquaporins) through which water and some
drugs can diffuse. However, the number and size of the
pores vary greatly between different membranes and the
membrane may have limited capacity to allow aqueous
diffusion. Aqueous diffusion can also be paracellular via
intercellular gaps. The epithelial cells lining the surface
of the body (e.g. gut, cornea and bladder) are connected
by tight junctions and only very small molecules can
pass through. In contrast, most capillaries have very
large pores and much larger molecules can pass along
hydrostatic and concentration gradients. An exception
to this is the capillaries of protected parts of the body
such as the choroid plexus and the blood–brain
barrier.
Lipid diffusion
One of the most important methods of drug permeation
is movement of molecules across cell membranes by
dissolution in the lipids of the membrane. The move-
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