Drug Distribution

M.M.
U COLLEGE OF
PHARMACY
RAMANAGARAM-571511
SEMINAR ON
DRUG DISTRIBUTION & FACTORS
AFFECTING
PRESENTED BY SUBMIT TO
AZIM ARSHI VASEEHA BANU.T.S
1ST M.PHARMA ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
1
DRUG DISTRIBUTION
SUBMIT TO VASEEHA BANU.T.S ASSISTANT PROFESSOR
Distribution Means Reversible Transfer of Drug(s)

from One Location to Another within Body. The
distribution of drugs from blood to tissue occurs at
various rate and to various extent. Following factor
Determine the distribution pattern of drug such
as:-
Affinity of drug
PRESENTED BY AZIM ARSHI, 1ST M.PHARMA
Ability of drug to pass through tissue membrane

Binding of drug to both plasma protein and

tissue component
2
DRUG DISTRIBUTION PATTERNS
Distribution can be through of as following one of

four types of patterns
BODY WATER
IN VARIOUS
ORGEN
2
SPECIFIC
BLOOD 1 4 3 ORGEN
TISSUE E.g.
Fat
General Organ E.g.

Liver Muscle
3
Distribution Patterns
1)The drug May remain

largely with in the
vascular system.
2)Some Low molecular
weight water soluble
compound such as
Ethanol, & few

sulphonamides become
uniformly Distributed
through the body water.
4
Distribution Patterns
3)
3) AA few
few drug
drug are
are concentrated
concentrated
specifically
specifically inin 11 or
or more
more tissue
tissue
that
that may
may or or may
may not
not bebe site
site of
of
action.
action.
4)
4) Most
Most drug
drug exhibit
exhibit aa non-uniform
non-uniform
distribution
distribution in in the
the body
body with
with the
the
variations
variations that
that is
is largely
largely
determination
determination by by their
their ability
ability to
to
pass
pass through
through the the membrane
membrane
&their
&their lipid/water
lipid/water solubility.
solubility. The
The
highest
highest concentration
concentration are are often
often
present
present inin Kidney,
Kidney, Liver,
Liver,
5
FACTORS AFFECTING DRUG DISTRIBUTION

Rate of distribution
Rate of distribution
Extent of distribution
Membrane permeability (Capillaries Membrane
permeability)
Blood perfusion rate
6
Membrane permeability
(Capillary Membrane
permeability)
Membrane Permeability tends to restrict the transfer & distribution of

drug once they are delivered to the tissues
The capillaries are typically lined

with endothelium whose cells
overlap,. Also, the junctions between
cells are discontinuous. Capillary
walls are quite permeable
Lipid soluble drugs pass through

very rapidly.
Water soluble compounds
penetrate more slowly at a rate more
dependent on their size.
7
Membrane permeability
(Capillary Membrane
permeability)
Low molecular weight drug pass

through simple diffusion
For compound with molecular
diameter above 100 transfer is
slow
For drugs which can be ionized the
drug's pKa and the pH of the blood
will have a large effect on the

transfer rate across the capillary

membrane.
8
There are two
There are two deviations
deviations to
to the
the typical
typical capillary
capillary structure
structure
which
which result
result in
in variation
variation from
from normal
normal drug
drug tissue
tissue permeability
permeability
Permeability is
greatly increased in
the renal capillaries
by pores in the
membrane of the
endothelial cells,
and in specialized
hepatic capillaries,
ane known as sinusoids

br
em which may lack a
m
s in complete lining.
ore
P
9
There are two
There are two deviations
deviations to
to the
the typical
typical capillary
capillary structure
structure
which
which result
result in
in variation
variation from
from normal
normal drug
drug tissue
tissue permeability
permeability

On
On the
the other
other hand
hand brain
brain
capillaries
capillaries seem
seem to to have
have
impermeable
impermeable walls
walls
restricting
restricting the
the transfer
transfer of
of
molecules
molecules from
from blood
blood toto
brain
brain tissue.
tissue. Lipid
Lipid soluble
soluble
compounds
compounds can can bebe readily
readily
transferred
transferred But
But the
the
transfer
transfer of
of polar
polar
substances
substances is is severely
severely
restricted.
restricted. This
This is is the
the
basis
basis of
of the
the "blood-brain"
"blood-brain"
barrier
barrier
10
That
That means
means Membrane
Membrane Permeability
Permeability depend upon Physico-
depend upon Physico-
Chemical
Chemical Properties
Properties such
such as
as molecular
molecular size,
size, lipid
lipid solubility,
solubility,
And
And Physiologic
Physiologic Barriers
Barriers such
such as.
as.
Simple
Simple capillary
capillary Simple
Simple cell
cell membrane
membrane
endothelial
endothelial barrier
barrier barrier
barrier
Blood
Blood Brain
Brain barrier
barrier Cerebrospinal
Cerebrospinal barrier
barrier
Placenta
Placenta barrier
barrier Blood-Testis
Blood-Testis barrier
barrier
11
Simple
Simple capillary
capillary
endothelial
endothelial barrier
barrier
All
All the
the Drug,
Drug, ionized
ionized or
or
unionized
unionized with
with a
a
molecular
molecular size size 600
600
Dalton,
Dalton, diffuse
diffuse through
through
the
the endothelium
endothelium and and
into
into the the interstitial
interstitial
fluid.
fluid. Only
Only drugs
drugs bound
bound
the
the blood
blood component
component
are
are restricted
restricted because
because
of
of the
the large
large molecular
molecular
size
size of
of complex
complex
12
Blood
Blood Brain
Brain barrier
barrier
The
The brain
brain capillaries
capillaries consist
consist of
of endothelial
endothelial cell
cell which
which
are
are joined
joined to to one
one another
another byby continuous
continuous tight
tight
intracellular
intracellular junction
junction comprising
comprising what
what is
is called
called as
as blood
blood
brain
brain barrier.
barrier.
13
Cerebrospinal
Cerebrospinal barrier
barrier
CSF
CSF is
is formed
formed mainly
mainly by
by choroid
choroid plexus
plexus of
of the
the lateral,
lateral, 3
rd
3rd
&
& 4
4th ventricles
th
ventricles &
& similar
similar in
in composition
composition to
to the
the EHF
EHF of of
brain.
brain.
14
Placenta
Placenta barrier
barrier
The
The maternal
maternal & & the
the fetal
fetal blood
blood vessels
vessels are
are separated
separated by
by
number
number of
of tissue
tissue layer
layer made
made of
of fetal
fetal trophoblast
trophoblast basement
basement
membrane
membrane & & endothelium
endothelium which
which together
together constitute
constitute the
the
placental
placental barrier.
barrier.
15
Blood perfusion rate
Perfusion
Perfusion rate is define as
volume of blood that
flows/minute/tissue volume.
Perfusion rate of tissue varies
from approximately
10ml/min/ml for lungs to 0.025
ml/min/ml form muscle or fat.

16
PRESENTED BY AZIM ARSHI, 1ST M.PHARMA SUBMIT TO VASEEHA BANU.T.S ASSISTANT PROFESSOR
Poor Moderator
Moderator perfusion
Poor perfusion
perfusion perfusion
High
High perfusion
perfusion
Organ
FAT
LUNGS
SKIN
BONE
LIVER
BRAIN
HEART
KIDNEY
MUSCLES
5000
250
200
700
200
350
1350
1250
1000
organs
(ml/min)
Blood flow
10.2
rate
0.5
0.6
0.8
4.5
0.02
0.03
0.033
0.025
Perfusion
(ml/min/ml)
Blood perfusion rate in various
17
Total blood flow is greatest to As an example; thiopental

brain, kidneys, liver, and
gets into the brain faster
muscle with highest perfusion
than muscle, whereas,
rates to brain,
penicillin gets into muscle
kidney, liver, and heart. It
more quickly than it gets into
would be expected that
brain
total drug concentration Thiopental is only partly
would rise most rapidly in
ionized and passes into the
these organs. Certain smaller

brain or muscle easily.
organs such as the
Perfusion limits the transport.

adrenals (1.2 - 5.5 ml/min/ml
Since brain has a higher
or 0.2 - 1% CO) and thyroid
perfusion rate the thiopental
(2.4 - 4 ml/min/ml or 1 - 2%
can transfer in and out more
CO) also have large perfusion
quickly
rates.
18
Penicillin
Penicillin is
is quite
quite polar
polar thus
thus slowly
slowly permeable.
permeable.
Permeability
Permeability limited
limited transfer
transfer is
is faster
faster in
in muscle
muscle as
as
muscle
muscle capillaries
capillaries are
are less
less restrictive.
restrictive. Thus
Thus
transfer
transfer of
of penicillin
penicillin is
is faster
faster in
in muscle
muscle than
than brain
brain
19
Extent of distribution
PLASMA PROTEIN
BINDING TISSUE BINDING
APPARENT
VOLUME OF
DISTRIBUTION
DRUG BINDING TO
ERYTHROCYTES
20
PLASMA PROTEIN BINDING
Binding of drug to plasma protein is most

common 50% of the total proteins bind the
widest range of drugs. The acidic drugs

commonly tend to bind with albumin where as

basic drug often bind to alpha and glycoprotein
and lipoprotein.
21
PROTEINS WITH POTENTIAL BINDING
SITES FOR VARIOUS DRUGS
Acidic Basic
Drug drug
Binding site Albumins Globulins, 1,
2, 1, 2,
Example Bilirubin, Bile Adenisine,
Drug
acids, Fatty Quinacrine,
Acids, Vitamin Quinine,
C, Salicylates, Streptomycin,
Sulfonamides, Chloramphenic
Barbiturates, ol, Digitoxin,
Phenylbutazone Ouabain,
22
, Penicillins, Coumarin
FACTOR INVOLVED
Groups on the protein molecules that are

responsible for electrostatic interactions with
drugs include
the NH33++ of lysine and N-- terminal amino acids
the NH22++ of histidine,
the COO-- of glutamic acid residues
The initial electrostatic attraction is reinforced by

van der Waal's forces and hydrogen bonding
23
FACTOR INVOLVED
Example
Phenyllbutazone and Salicylates displace
tolbutamide to give an increased effect,
hypoglycemia
The displacement of warfarine by phenyl
butazone leads to nearly 100 folds increase in
free drug con. Which can result in clinical
significant reaction.
The value of the fraction of drug in plasma

that is unbounded to plasma proteins, f is u
u
given by
u
uf = C /C
u
u
24
PERCENT UNBOUND FOR SELECTED DRUGS
Drug Percent Unbound (100 * fu)

Digoxin 77
Gentamicin 90
Theophylline 85
Phenytoin 11 - 13
Diazepam 3-4
Warfarin 0.5
Phenylbutazone 1-5
Dicumarol 1-3 25
TISSUE BINDING
a) Specific protein in
tissues
Example
b) Accumulation in
The con. Of chloroquine
endocytotic vesicles
in the liver is due to
(E.g. Gentamycin in
the binding of drug to
renal proximal tube)
DNA. Paracetamol
c) Binding to nucleic
bind irreversibly to
acid
liver tissue resulting
d) Binding to Calcium
hepatotoxicity
e) Accumulation in lipid
depots
30
APPARENT VOLUM OF DISTRIBUTION
The extent of distribution is indicated by apparent

of distribution
Vdd =
=AABB = Amount of drug in body
Cpp Amount of drug in the plasma
The volume of distribution varies from 7- 40,0001
per 70 kg body weight
The amount of drug in plasma VppCpp

The amount of drug in plasma VddCpp
31
APPARENT VOLUM OF DISTRIBUTION
Fraction of drug in body plasma = Vd/Vp

Fraction of drug in body outside plasma = Vd Vp
Vd
Percent unbound in body =

total body water X 100

Vuu
32
DRUG BINDING TO ERYTHOCYTES
Drug
Drug like
like phenytoine
phenytoine ..etc
..etc bind
bind to
to
Hemoglobin hemoglobin
hemoglobin
Drug
Drug like
like Acetazolamide,
Acetazolamide,
Carbonic anhydrase Chlorthalidone
Chlorthalidone
Imipramine &
RBC membrane Chlorpromazine
33
factor
Age
Miscellaneous
Obesity
Pregnancy
Diet
Drug
interaction
34
REFERENCES
D.M.BRAHMANKAR, SUNIL B.JAISWAL P 76-90
Dr.SHOBHA RANI , P 138-150
Rowland, M. and Tozer, T.N, 1995 Clinical
Pharmacokinetics Concepts and Applications, 3rd
ed., Williams & Williams. Media, PA
Shargel, L., Wu-Pong, S. and Yu, A.B.C. 2005
Applied Biopharmaceutics and Pharmacokinetics,
5th ed., McGraw-Hill, New York, NY
Niazi, S. 1979 Textbook of Biopharmaceutics and
Clinical Pharmacokinetics, Appleton-Century-

Crofts, New York, NY p101
35
Ritschel, W.A. and Kearns, G.L. 2004 Handbook of
Basic Pharmacokinetics ... including Clinical
Applications, 6th ed., American Pharmaceutical

Association, Washington, DC, pp369-401
chignell, C.F. 1973 Ann. New York Acad. Sci., 226,
p49, 53
Abernethy, D.R., Greenblatt, D.J, Divoll, M. et al.
1981 Alterations in drug distribution and clearance

due to obesity, J.P.E.T., 217, p681-85
Rowland, M and Tozer, T.N. 1989 Clinical
Pharmacokinetics, Lea & Febiger, Philadelphia, pp

260-270
These book available on
http://www.boomer.org/c/p4/c18/c1802.html
http://www.boomer.org/c/p1/Ch18/Ch1802.html
36
THANKYOU
37

Drug Distribution

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Drug Distribution

Uploaded by

Copyright:

Available Formats

M.M.

Distribution Means Reversible Transfer of Drug(s)

Ability of drug to pass through tissue membrane

Binding of drug to both plasma protein and

Distribution can be through of as following one of

General Organ E.g.

1)The drug May remain

Ethanol, & few

Membrane Permeability tends to restrict the transfer & distribution of

The capillaries are typically lined

Lipid soluble drugs pass through

Low molecular weight drug pass

will have a large effect on the

transfer rate across the capillary

ane known as sinusoids

ml/min/ml form muscle or fat.

Total blood flow is greatest to As an example; thiopental

these organs. Certain smaller

Perfusion limits the transport.

Binding of drug to plasma protein is most

widest range of drugs. The acidic drugs

commonly tend to bind with albumin where as

Groups on the protein molecules that are

The initial electrostatic attraction is reinforced by

The value of the fraction of drug in plasma

Drug Percent Unbound (100 * fu)

The extent of distribution is indicated by apparent

The amount of drug in plasma VppCpp

The amount of drug in plasma VddCpp

Fraction of drug in body plasma = Vd/Vp

Percent unbound in body =

total body water X 100

Clinical Pharmacokinetics, Appleton-Century-

Applications, 6th ed., American Pharmaceutical

1981 Alterations in drug distribution and clearance

Pharmacokinetics, Lea & Febiger, Philadelphia, pp

These book available on

You might also like