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Chapter 3
PHARMACOKINETICS
“What the body does to the drug”
Lei Wang
Department of Pharmacology
Absorption ：the movement of a drug from its
site of administration into the circulation.
Distribution ：the movement of a drug leaving
the bloodstream and going into the organs and
tissues.
A
D
M
E
2
Metabolism(Biotransformation) : chemical
alteration of the drug structure mediated by enzyme,
primarily in the liver.
Excretion: the movement of drugs and their
metabolites out of the body primarily by the kidneys.
Elimination: the combination of metabolism and
excretion. A
D
M
E
Transmembrane Transport of Drugs
Filtration
Simple
Diffusion
Specialized
Transport
Facilitated
Diffusion
Active
Transport
Simple Diffusion (Passive Diffusion )





Most drugs are transported across the membranes
by passive diffusion
Diffuses across the membrane in the direction of
drug’s concentration gradient
Diffusion rate is directly proportional to the
gradient
No need of energy
No a carrier is involved
Simple Diffusion (Passive Diffusion )

Passive diffusion depends on the molecule's
lipid solubility, size, degree of ionization, and
the area of absorptive surface.
Simple Diffusion (Passive Diffusion)
Cell Membrane Structure
Biological membranes are
bilayer, phospholipids
matrices containing
cholesterol, protein, and
other constituent.
The membranes are
primarily lipid in nature.
“like dissolves like”
a solute will dissolve
best in a solvent that
has a similar chemical
structure to itself.
Only lipid soluble drugs
can dissolve in the lipid
membrane and penetrate the
membrane.
Lipid soluble drugs
Polar molecules and ions are
not lipid soluble and cannot
Water soluble drug penetrate membranes by
simple diffusion.
Simple Diffusion (Passive Diffusion)
Effect of pH on passive diffusion
Many drugs are weak acids or weak bases
 Weak acids and weak bases exist in solution as
a mixture of ionized and un-ionized forms
Weak Acid HA
H+ + A (unionized)
(ionized)
(cross membrane)

Only the unionized
(uncharged) form of a
Nonionized = Lipid soluble drug can cross cell
membranes
Ionized = Water soluble
Simple Diffusion (Passive Diffusion)
The proportion of
unionized drug depends
on the pKa (dissociation
constant) of the drug and
the environmental pH.
pKa : pH at which
50% of the drug is
ionized and 50% is
un-ionized.
Simple Diffusion (Passive Diffusion)
Handerson-Hasselbalch Equation
For acids (A)：
For bases (B)：
Simple Diffusion (Passive Diffusion)
Effect of the environment pH on
the degree of ionization


A weak acid will be unionized when in an
acidic environment, and a weak base will be
unionized in a basic environment.
A weak acid will be ionized when in a basic
environment, and a weak base drug will be
ionized in an acidic environment.
Simple Diffusion (Passive Diffusion)
In the stomach (pH 2.0)，which will be better
absorbed, a weak acid (pK 6.8) or a weak base
(pK 7.1)?


A weak acid is most likely to be unionized
when in an acidic environment
An alkaline drug is preferentially ionized in an
acidic environment.
Weak acid
Simple Diffusion (Passive Diffusion)
Weak
acids can also be absorbed more readily
from the intestines than from the stomach,
despite their greater ionization in the intestines
The
greater surface area in the intestines
outweighs the influence of greater ionization in
the intestines.
Most
drugs are absorbed in the intestines
Passive Tubular Reabsorption
The reabsorption of drug from the lumen of the
distal convoluted tubules into plasma occurs by
simple diffusion.
Urine pH determines the ionization state of a
weak acid or base, and changes in urinary pH may
markedly affect drug reabsorption and excretion.
Passive Reabsorption
Passive reabsorption
of lipidsoluble, unionized drug
Ionized or
polar
metabolite
Simple Diffusion (Passive Diffusion)
Ion Trapping


Ion trapping occurs with weak acids and weak
bases if there is a difference in pH on two sides
of a membrane.
The ionized form of the drug will be trapped
on one side of a membrane where the ionized
form is predominant.
Ionized form
Nonionized form
lipid
NH3
NH3
H+
H+
H+
PH 7.4
PH 7.0
H+
NH3
H+
H+
NH3
H+
NH3
NH3
NH3
Once the unionized basic drug
crosses the cell membrane to
enter the cell, it becomes
ionized
NH3 + H+ ⇌ NH4+
NH4+
PH 7.0
NH4+
NH4+
NH4+
PH 7.4
NH4+
NH4+
NH4+
AA-
A-
NH4+
NH4+
A-
PH 7.0
A-
NH4+
NH4+
NH4+
ANH4+
PH 7.4
Ion trapping
results in basic
drug’s
accumulating in
acidic bodily
fluids and acidic
drug’s
accumulating in
basic fluids.
Filtration
Filtration is passage of drugs through aqueous
pores in the membrane or through paracellular
spaces.
Aqueous
Diffusion
Filtration
Aqueous Diffusion


Water can cross cell membranes through
aqueous pores.
Bulk flow of water can carry with it drug
molecules.
Aqueous
Diffusion
Bulk Flow
Aqueous Diffusion
Only those drugs whose molecular size is
smaller than the diameter of the pores may
pass through the aqueous pores.
 Majority of cells have very small pores and
drug with molecular weights (MW) exceeds
100 to 200 daltons are not able to penetrate.
 Aqueous diffusion is restricted to drugs with
low molecular weights; many drugs are too
large to penetrate the
membrane by this process.

Paracellular Transport
Passing
Filtration
through the intercellular space between
the cells.
Involved in
Capillaries
capillaries.
(except those in brain)
have large paracellular space and most drug can
filter through these.
Be
Be
limited to unbound drug.
an important factor in filtration across
glomerular membranes in the kidney.
Distribution
Plasma Protein Binding
Glomerular Filtration
 Serum
protein binding reduces filtration because
plasma proteins are too large to be filtered.
Carrier-Mediated Membrane Transport
Be specific for the substrate (selectivity)
Carrier transport have arisen during evolution
to carry naturally occurring molecules
In reality very few drugs can cross the
membrane by this method
Be saturable.
Competitively inhibited by analogues which
utilize the same transporter.
Facilitated Diffusion
 It
means the passage of drug across the
biological membrane along the concentration
gradient by the protein carrier mediated system
also called as carrier mediated diffusion.

Example: Cephalexin undergo facilitated diffusion by
an oligopeptide transporter protein located in
intestinal
Active Transport
The process by which drugs pass across the
biological membrane most often against their
concentration gradient with the help of
carriers along with the expenditure of energy.
In all cells, active transport
usually accumulates some
molecules that the cell needs,
such as ions, glucose and
amino acids.
Active Tubular Secretion
Characteristics of active transport are:
a. Saturability of the carrier
b. Competition between substrates for the
carrier
penicillin penicillin penicillin
Example:
OATs
OATs
OATs
penicillinprobenecid probenecid
OATs
OATs
Penicillin and Probenecid
Using acid pathway
Decreasing excretion of penicillin
Increasing action duration of penicillin
OATs
ADME
Transmembrane transport
Simple diffusion
lipid solubility
degree of ionization
Ion trapping