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
Distribution Means Reversible Transfer of Drug(s)

PRESENTED BY AZIM ARSHI, 1ST M.PHARMA SUBMIT TO VASEEHA BANU.T.S ASSISTANT PROFESSOR
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
 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
BLOOD 1 SPECIFIC
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) A few drug are concentrated

specifically in 1 or more tissue that
may
may oror may
may not
not be
be site
site of
of action.
action.
4) Most drug exhibit a non-uniform
distribution in the body with the
variations
variations that
that is
is largely
largely determination
determination
by their ability to pass through the
membrane &their lipid/water
solubility. The highest concentration

are often present in Kidney, 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 Å 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
There are
are two
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, known as
a ne sinusoids which may

m br lack a complete lining.
m e
s in
ore
P
9
There
There are
are two
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 thethe other
other hand
hand brain
brain
capillaries
capillaries seemseem to to have
have
impermeable
impermeable wallswalls restricting
restricting
the
the transfer
transfer ofof 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 ofof the
the "blood-brain"
"blood-brain"
barrier
barrier
10
That
That means
means Membrane
Membrane Permeability
Permeability depend
depend upon
upon Physico-Chemical
Physico-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 endothelial
endothelial Simple
Simple cell
cell membrane
membrane
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 capillary
endothelial barrier
All the Drug, ionized or

unionized with a molecular
size 600 Dalton, diffuse
through the endothelium
and into the interstitial
fluid. Only drugs bound
the blood component are
restricted because of the
large molecular size of
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 isis formed
formed mainly
mainly by
by choroid
choroid plexus
plexus of
of the
the lateral,
lateral, 33rd &
rd
& 44th
th
ventricles
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 ofof 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
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
(ml/min)
Blood flow
10.2
0.5
0.6
0.8
4.5
0.02
0.03
0.033
0.025
(ml/min/ml)
Perfusion rate
Blood perfusion rate in various organs
17
Total blood flow is greatest to

brain, kidneys, liver, and
 As an example; thiopental gets
muscle with highest perfusion
into the brain faster
rates to brain,
than muscle, whereas, penicillin
kidney, liver, and heart. It would
gets into muscle
be expected that
more quickly than it gets into brain
total drug concentration would rise
 Thiopental is only partly
most rapidly in
ionized and passes into the brain or
these organs. Certain smaller
muscle easily. Perfusion limits the
organs such as the
transport. Since brain has a higher

adrenals (1.2 - 5.5 ml/min/ml or
perfusion rate the thiopental can
0.2 - 1% CO) and thyroid
transfer in and out more quickly
(2.4 - 4 ml/min/ml or 1 - 2% CO)
also have large perfusion 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 Drug Basic drug

Binding site Albumins Globulins, α1, α2,

β1 , β2 , γ
Example Drug Bilirubin, Bile Adenisine,
acids, Fatty Acids, Quinacrine,
Vitamin C, Quinine,
Salicylates, Streptomycin,
Sulfonamides, Chloramphenicol,
Barbiturates, Digitoxin,
Phenylbutazone, Ouabain,
Penicillins, Coumarin
Tetracyclines,
Probenecid
22
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 given by

u
u
f = C /C
u
u 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 in
endocytotic vesicles
the liver is due to the
(E.g. Gentamycin in
binding of drug to DNA.
renal proximal tube)
Paracetamol bind
c) Binding to nucleic acid
irreversibly to liver tissue
d) Binding to Calcium
resulting hepatotoxicity
e) Accumulation in lipid
depots
30
APPARENT VOLUM OF DISTRIBUTION
The extent of distribution is indicated by apparent of

distribution
Vd = ABB = 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 like Acetazolamide,

Carbonic anhydrase Chlorthalidone
RBC membrane Imipramine & Chlorpromazine
33
Age
Miscellaneous factor
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

Copyright:

Available Formats

You might also like

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)

from One Location to Another within Body. The

 Ability of drug to pass through tissue membrane

 Binding of drug to both plasma protein and tissue

Distribution can be through of as following one of four

General Organ E.g.

1) The drug May remain

3) A few drug are concentrated

solubility. The highest concentration

they are delivered to the tissues

The capillaries are typically lined with

Water soluble compounds penetrate

 Low molecular weight drug pass

a ne sinusoids which may

All the Drug, ionized or

Total blood flow is greatest to

transport. Since brain has a higher

Binding of drug to plasma protein is most common

albumin where as basic drug often bind to alpha and

Acidic Drug Basic drug

Binding site Albumins Globulins, α1, α2,

Groups on the protein molecules that are responsible for

The initial electrostatic attraction is reinforced by van der

Waal's forces and hydrogen bonding

unbounded to plasma proteins, f is given by

Drug Percent Unbound (100 * fu)

The extent of distribution is indicated by apparent of

Fraction of drug in body plasma = Vd/Vp

Percent unbound in body =

Drug like Acetazolamide,

RBC membrane Imipramine & Chlorpromazine

DR.SHOBHA RANI , P 138-150

BIOPHARMACEUTICS AND CLINICAL

 Abernethy, D.R., Greenblatt, D.J, Divoll, M. et al. 1981

You might also like