Lecture 7
PHARMACOKINETICS
Drug at site
of administration
Absorption
Drug in plasma
Distribution
Drug/metabolites
in tissues
Metabolism
Drug/metabolites
in urine, feces, bile
Elimination



Definition :
The process of movement of
unchanged
drug
from
the
site
of
administration to systemic circulation.
The ultimate goal is to have the drug reach the
site of action in a concentration which
produces a pharmacological effect.
No matter how the drug is given (other than IV)
it must pass through a number of biological
membranes before it reaches the site of action.
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
Blood Flow To Absorptive Site:
o
Greater blood flow raises absorption
Intestine has greater BF than stomach

Total Surface Area of Absorptive Site:
o


Intestinal microvilli increases surface area to 1000fold that of the stomach favoring intestinal
absorption
Contact Time at Absorptive Site:
Diarrhea reduces absorption
 Accelerated gastric emptying→ faster delivery to
intestinal large surface → increased absorption







Food: Presence of food in the gut reduces/delays
drug absorption from GIT
Increased splanchnic blood flow during eating
increases drug absorption
Ionized drugs as tetracycline can form insoluble
complexes with Ca2+ in food/milk.
Formulation Factors:
Solid dosage forms dissolution & solubility are
essential
Aqueous solutions are absorbed more quickly than
tablets or suspensions
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Drug transported by passive diffusion
depend upon:

dissociation constant, pKa of the drug
 pH at absorption site.


lipid solubility,
K o/w. Polarity estimates partition
coefficient. The greater the lipid solubility – the faster the rate
of diffusion


Most drugs are either weak acids or weak
bases whose degree of ionization is depend
upon pH of biological fluid.



For a drug to be absorbed, it should be
unionized and the unionized portion should
be lipid soluble. Only non-ionized fraction of
drugs (acids or bases is absorbed
The fraction of drug remaining unionized is a
function of both
Dissociation constant (pKa) and pH of
solution.
HENDERSON HASSELBATCH EQUATION
For acid,
For base,
pKa - pH = log[ Cu/Ci ]
pKa – pH = log[ Ci/Cu ]
Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will
have > 99%of unionized form so gets absorbed in
stomach
Weak base quinine (pKa=8.5) will have very negligible
unionization in gastric pH so negligible absorption
Several prodrugs have been developed which are lipid
soluble to overcome poor oral absorption of their
parent compounds.
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◦ Absorption facts:
Smaller molecules penetrate more rapidly.
The membrane is Highly permeable to O2, CO2, NO and H2O .
Large polar molecules – sugar, amino acids, phosphorylated
intermediates – poor permeability. These are essential for
cell function, and thus must be actively transported
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KLECOP, Niani
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1) Passive diffusion
2) Carrier- mediated transport
a) Facilitated diffusion
b) Active transport
3) PINOCYTOSIS
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08/10/2010
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



Also known as nonionic diffusion.
It depends on the
difference in the drug
concentration on either
side of the membrane.
Absorption of 90% of
drugs.
The driving force for
this process is the
concentration
or
electrochemical
gradient.
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


Involves a carrier (a component of the
membrane) which binds reversibly with the
solute molecules to be transported to yield
the carrier solute complex which transverses
across the membrane to the other side where
it dissociates to yield the solute molecule
The carrier then returns to its original site to
accept a fresh molecule of solute.
There are two types of carrier mediated
transport system:
a) facilitated diffusion
b) active transport
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

This
mechanism
driving
force
is
concentration
gradient.
In this system, no
use of energy is
involved (down-hill
transport), therefore
the process is not
inhibited
by
metabolic
poisons
that interfere with
energy production.
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



More important process
than facilitated diffusion.
The
driving
force
is
against the concentration
gradient
or
uphill
transport.
Since the process is uphill,
energy is required in the
work done by the barrier.
As the process requires
energy, it can be inhibited
by metabolic poisons that
interfere
with
energy
production.
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Active transport:
• Carrier-mediated
• Energy-dependent
• Against conc gradient
• Shows carrier
saturation kinetics
 Passive transport
• Energy-independent
• No carrier involved
• Along conc gradient
• No saturation kinetics

ATP
ADP
+ Pi
AH
B
ABH+
Carrier-mediated
energy-dependent
active transport
Passive diffusion
of a water-sol
drug via aqueous
channel
Passive diffusion
of a lipid-sol drug

This process is
important in the
absorption of oil
soluble vitamins &
in the uptake of
nutrients.
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
the proportion of the drug in a dosage
form available to the body
 Fraction
of a drug reaching
systemic circulation in chemically
unchanged form after a particular
route
 First pass metabolism, i.e., rapid
hepatic metabolism, reduces bioav.
(lidocaine, propranolol, nitrates)
Drug solubility
 Chemical
instability in
gastric pH (penicillin G,
insulin)
 Drug
formulation:
Standard
&
SR
formulations

Serum
Concentration

Bio = AUC oral/AUC IV x 100
Injected Dose
Oral Dose
Time
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Therapeutic success
of a rapidly &
completely absorbed
drug.
Plasm
a
Minimum effective
conc.
Therapeutic failure of
a slowly absorbed
drug.
Drug
Conc.
Not
only
the
magnitude of drug that
comes
into
the
systemic
circulation
but also the rate at
which it is absorbed is
important this is clear
from the figure.
Subtherapeutic
level
Time
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