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Biopharmaceuti

cs &
Pharmacokineti
cs
Lecturer: Dr. Muslim Suardi,
M.Si, Apt
Difusion of drug
Kelompok 2
1. Nova Lestari (1411011043)
2. Rama saputri (1411011046)
3. Anna fadhila (1411011049)
4. Nur Azlin (1411011061)
5. Suci Dita Ramadhani (1401101164)

Pharmacokinetics is the quantitative study of


drug movement in, through and out of the
body.
Intensity of effect is related to the
concentration
of the drug at the site of action, which
depends
on its pharmacokinetic properties.

Pharmacokinetic properties of the drug


determine the route(s) of administration, dose,
latency of onset, time of peak action, duration
(Dhillon, S. Basic Pharmacokinetics)
of
action
and
frequency
of
drug

. ABSORPTION
It is the passage of drug from
the site
of administration into the
circulation.

Aqueous solubility. Drugs given in solid form


must
dissolve in the aqueous biophase before they
are
absorbed. For poorly water soluble drugs
(aspirin,
griseofulvin) the rate of dissolution governs the
rate
(Dhillon,
Basic
Pharmacokinetics).
of absorption. If a drug is
givenS.as
water
solution,

The mechanism of transfer /


transport drugs
Passive diffusion
Transfer of drugs / compounds of compartments
high concentration to low concentration
a transport mechanism of most drugs
Active Transport
Transfer of drugs / compounds of compartments
low concentration to high concentration
requires energy and protein carrier / carrier
transport mechanisms of certain drugs

(Atkinson, A. J. 2007)

(Atkinson, A. J. 2007)

Passive diffusion:
Depending on:
the size and shape of the molecule
drug
solubility in fat
the degree of ionization of drugs

(Atkinson, A. J. 2007)

The influence of the drug solubility in lipids


The cell membrane is composed of lipid molecules
(fat)
Consequently, the drug is soluble in lipids (lipid
soluble) will
diffuses through the membrane more easily than
drugs
soluble in water (water soluble)
The solubility of the drug in the lipid
expressed as partition coefficient (P)
figures showing comparison of the drug solubility
in
lipid and water
P = ratio of ionized drugs distributed in the water
phase
and lipids in the equilibrium state (equilibrium).
(Atkinson, A. J. 2007)
Po / w = (Coil / Cwater) equilibrium

degree of ionization
Is that many drug-ionised (being
charged)
when dissolved in water
The main determining factor of
ionization:
acid-base properties of drugs: a
weak acid or weak base
(Most drugs are weak acids or weak
bases)
acid-base properties of a liquid
solvent (solvent) was: acid or
alkali
(Weakly acidic drug will be ionized
(Atkinson, A. J. 2007)
at

Examples of the drug and the nature of acidity

Absorption in the Blood-Brain Barrier


(Blood brain barrier)
Especially for drugs where the action is
in the brain, he must can penetrate the
blood-brain barrier To the blood brain
barrier: protect the brain from materials
may be dangerous.
To be able to penetrate the blood-brain
barrier,
a drug must:
not ionised at the pH of blood
Memiliki high partition coefficient
(soluble
lipid)
or, using the help of a
transport mechanisms (ex : L-DOPA)
(Atkinson, A. J. 2007)

(Atkinson, A. J. 2007)

Passage of drug across the


placenta
The placenta is not an effective parrier to
most drugs. This is why the utmost care
must be taken when administering drugs to
pregnant animals. Only highly ionized drugs
and drugs with low lipid solubility are
excluded. Drugs such as oxytocin are
vulnerable to placental enzymes and so do
not pose such a risk to the fetus.
(Atkinson, A. J. 2007)

II. DISTRIBUTION
Distribution is the process by which
a drug diffuses or is transferred
from
intravascular
space
to
extravascular space (body tissues).

(Reddy, M. B., dkk. 2005).

Drug distribution
Drug molecules are distributed to eliminating
organs, such as the liver and kidney, and to
noneliminating tissues, such as the brain,
skin, and muscle.
In pregnancy, drugs cross the placenta and
may affect the developing fetus. Drugs can
also be secreted in milk via the mammillary
glands. A substantial portion of the drug may
be bound to proteins in the plasma and/or
tissues. Lipophilic drugs deposit in fat, from
which the drug may be slowly released.
(Reddy, M. B., dkk. 2005).

Diffusion and Hydrostatic Pressure


The processes by which drugs
transverse
capillary
membranes
include
passive
diffusion
and
hydrostatic
pressure.
Passive
diffusion is the main process by
which
most
drugs
cross
cell
membranes. Passive diffusion () is
the process by which drug molecules
move from an area of high
concentration to an (Reddy,
areaM. B.,ofdkk. 2005).
low

Cp Ct is the difference between the


drug concentration in the plasma (C p)
and in the tissue (C t)
A is the surface area of the membrane
h is the thickness of the membrane
K is the lipidwater partition coefficient
D is the diffusion constant

The factors that determine the


distribution constant of a drug into
an organ are related to:
The blood flow to the organ
The volume of the organ, and
The partitioning of the drug into the
organ tissue

(Dhillon, S. Basic Pharmacokinetics).

.Blood Flow
The rate at which a drug reaches different
organs and tissues will depend on the blood
flow to those regions. Equilibration is rapidly
achieved with heart, lungs, liver, kidneys and
brain where blood flow is high. Skin, bone,
and depot fat equilibrate much more slowly.
Lipid Solubility
Lipid solubility will affect the ability of the drug to
bind to plasma proteins and to cross lipid
membrane barriers.
Very high lipid solubility can result in a drug
initially partitioning preferentially into highly
vascular lipid-rich areas. Subsequently these
drugs slowly redistribute into body fat where they
Katzung. Clinical Pharmacology
may remain for long periods
of time.

Effects of pH
Effects of pH on the partitioning or "trapping" of
drugs will not be as dramatic as those seen
between the stomach and plasma since the pH
differences are not as great. Nevertheless, even
small pH differences have significant effects and so
acidic drugs will still tend to accumulate where the
pH is higher while bases do the reverse.

Katzung. Clinical Pharmacology

kd = first-order distribution constant


Q = blood flow to the organ
V = volume of the organ
R = ratio of drug concentration in the organ tissue to drug concentration in the
blood (venous)

The distribution half-life of the drug to


the tissue, t d1/2 may easily be
determined from the distribution
constant, t d1/2 = 0.693/kd
(Dhillon, S. Basic Pharmacokinetics).

Drug Accumulation
at steady state, the drug may or may not
accumulate (concentrate) within the tissue.
The accumulation of drug into tissues is
dependent on both the blood flow and the
affinity of the drug for the tissue
Drugs with a high lipid/water partition
coefficient are very fat soluble and tend to
accumulate in lipid or adipose (fat) tissue
Drugs may accumulate in tissues by other
processes
(Dhillon, S. Basic Pharmacokinetics).

Apparent Volume Distribution


The concentration of drug in the plasma
or tissues depends on the amount of drug
systemically absorbed and the volume in
which the drug is distributed. The
apparent volume of distribution, VD in a
model, is used to estimate the extent of
drug distribution in the body.
(Dhillon, S. Basic Pharmacokinetics).

Volume of distribution may vary between


drugs due to several factors:
pKa of drugs
pH of the medium
degree of binding to plasma proteins
and to tissue
proteins
lipid solubility
difference in regional blood flow
active transport.

(Dhillon, S. Basic Pharmacokinetics).

References
Aronson, J. K. 2005. Meylers Side Effects of Drugs. The
International Encyclopedia of Adverse Drug Reactions
and Interactions. 15th ed. Oxford, U.K: Elsevier
Atkinson, A. J., Abernethy, Jr. D. R., dkk. 2007. Principles
of Clinical Pharmacology 2nd edition. USA: Academic
Press of Elsevier.
Dhillon, Soraya and Gill, Kiren. Basic Pharmacokinetics.
Clinical Pharmacokinetics. Page: 5-8.
Katzung. Clinical Pharmacology
Reddy, M. B., Yang, R. S. H., Clewell, H. J., Andersen, M.
E. 2005. Physiologically Based Pharmacokinetics (PBPK)
Modeling. Science and Applications. U.S.A: John Wiley &
Sons, Inc, Publication.