B.

Pharmacy 6th Semester

BIOPHARMACEUTICS AND PHARMACOKINETICS (BP604T)

देव राज शर्मा

सहायक आचार्य
औषधि निर्माण विद्या विभाग
लॉरेट फार्मेसी संसथान कथोग
काँगड़ा
हि. प्र.
 DRUG DISTRIBUTION

Once a drug enter in to the blood stream, the drug is subjected to a

number of processes called as Disposition Processes that tend to
lower the plasma concentration.

1. Distribution which involves reversible transfer

of a drug between compartments.

2.Elimination which involves irreversible loss of

drug from the body.
It comprises of biotransformation and
excretion.
 DEFINITION

Drug Distribution is defined as the Reversible transfer of

drug between one compartment (blood) to another (extra
vascular tissue)
 Significance

Thus distribution plays important role in-

 Onset of Action
 Intensity of Action
 Duration of Action
 STEPS IN DRUG DISTRIBUTION
 Permeation of Free Drug through capillary wall & entry in to ECF.

 Permeation of drugs from ECF to ICF through membrane of

tissue cell.

Rate Limiting Steps

 Rate of Perfusion to the ECF

 Membrane Permeability of the Drug

DISTRIBUTION PROCESS
 *Distribution • The Process
is a Passive occurs by the
Process, Diffusion of
for which the Free Drug
until
Driving Force is equilibrium is
the Conc. established
Gradient between
the Blood and
Extravascular
Tissues
DISTRIBUTION OF DRUG IS NOT UNIFORM THROUGH OUT T
HE BODY- ---WHY?
Because tissue receive the drug from plasma at different rates
& different extents.
 FACTORS AFFECTING DISTRIBUTION OF DRUGS

1. Tissue Permeability of Drugs

 Physicochemical Properties of drug like
Mol.size, pKa, o/w Partition Coefficient
 Physiological barriers to diffusion of drugs

2. Organ/tissue size and perfusion rate

3. Binding of drugs to tissue components.

 binding of drug to blood components
 binding of drug to extra cellular components

4. Miscellaneous
 TISSUE PERMEABILITY OF DRUGS
Physicochemical Properties of drug
□ Molecular size,

□ pKa

□ o/w Partition Co Efficient.

Physiological barriers to Diffusion of Drugs

□ Simple Capillary Endothelial Barrier

□ Simple Cell Membrane Barrier

□ Blood Brain Barrier

□ Blood – CSF Barrier

□ Blood Placental Barrier

□ Blood Testis Barrier

 1). TISSUE PERMEABILITY
OF DRUG
a. Physicochemical property:
I) Molecular Size;
Mol. Wt. less then 500 to 600 Dalton easily pass
capillary membrane to extra cellular fluid.

Penetration of drug from ECF to cells is function of Mol

size, ionization constant & lipophilicity of drug

From extra cellular fluid to cross cell membrane through

aqueous filled channels need particle size less then 50
Dalton (small) with hydrophilic property .

Large mol size restricted or require specialized transport

system
 1). TISSUE PERMEABILITY OF DRUG
a. Physicochemical Property
ii) Degree of Ionization (pKa)
♫The pH at which half of a drug is unionized is called pKa
A weak acid becomes unionized in a strong acidic environment.
A weak acid becomes ionized in a neutral or basic environment.
&
A weak base becomes unionized in a strong basic environment.
A weak base becomes ionized in a neutral or acidic
environment.
BUT
The PH of Blood plasma, extra cellular fluid and CSF is
7.4( constant) Except in acidosis and alkalosis

All the drugs ionize at plasma pH (i.e. Polar , Hydrophilic Drugs)

Can not penetrate the Lipoidal cell membrane
 1). TISSUE PERMEABILITY OF DRUG
a. Physicochemical Property
iii) o/w permiability

 Polar and hydrophilic drugs are less likely to cross the cell
membrane
Where,,,,,,,,
 Nonpolar and hydrophobic drugs are more likely to cross
the cell membrane
EFFECTIVE KO/W = Fraction unionized x KO/W of unionized
at pH 7.4 drug
In case of polar drugs where permeability is the rate- limiting step in
the distribution , the driving force is the effective partition coefficient
of drug ……..that can be calculated by above formula
 Lipoidal drug penetrate the tissue rapidly. Among Drugs
with same Ko/w but diff in ionization of blood pH.

 One which has less ionization show better distribution.

E.g. Phenobarbital > salicylic acid
Both are having same Ko/w but phenobarbitol have
more unionized at blood pH

 highly specialized and less permeable

to water
soluble drugs.
 B. PHYSIOLOGICAL BARRIERS
1) The simple capillary endothelial barrier

Capillary supply the blood to the most inner tissue

All drugs ionized or unionized molecular size less than 600dalton
diffuse through the capillary endothelium to interstitial fluid

Only drugs that bound to that blood components can’t pass through
this barrier Because of larger size of complex
 B. PHYSIOLOGICAL BARRIERS

2. Simple cell membrane barrier

once the drug diffuse through capillary to extracellular fluid ,its
further entry in to cells of most tissue is limited.

Simple cell Membrane is similar to the lipoidal barrier (absorption)

Non polar & hydrophillic drugs will passes through it (passively).

Lipophilic drugs with 50 - 600 dalton mol size &

Hydrophilic, Polar drugs with ‹50dalton will pass this membrane

 B. PHYSIOLOGICAL
BARRIERS
3) Blood brain barrier
 B. PHYSIOLOGICAL BARRIERS
3) Blood brain barrier
Capillary in brain is highly specialized & much less
permeable to water soluble drugs
ENDOTHELIAL CELLS ;- Tightly bonded with each other by
intracellular junctions
ASTROCYTES :- present @ the base of endothelial tissue and
act as supporting materials
& it Form Envelop around the capillary thus intercellular
passage get blocked.

BBB is lipoidal barrier, thus drugs with high o/w partition

coefficient diffuse passively others (moderately lipid soluble
and partially ionised molecules passes slowly.
Polar natural substance (sugar & amino acid) transported to
brain actively thus structurally similar drug can pass easily to
BBB.
 DIFFERENT APPROACHES TO CROSS BBB
A) Permeation Enhancers ; - Dymethyl Sulfoxide
B) Pro- Drug Approach ; - Dopamine---- Levodopa
(Parkinsonism)
and osmatic disruption of the BBBBY infusing
internal carotid artery with mannitol
C)carrier system ; - Dihydropyridine (Lipid soluble) moiety
redox system (highly lipophilic & cross the BBB)
Complex formation (DRUG-DHP). After entering in
brain DHP gets metabolize by (CNS) enzyme in brain
and drug gets trapped in side the brain.
Polar pyridinium ion can not diffuse back out of the
brain.
Ex. Steroidal drug
 B. PHYSIOLOGICAL
4) BARRIERS
Cerebral spinal fluid
barrier
 B. PHYSIOLOGICAL BARRIERS
4) Cerebral Spinal Fluid Barrier;-
Capillary endothelial cells;- have open junction or gaps
so…. Drugs can flow freely b/w capillary wall & choroidal
cells.
Choroids plexus;- major components of CSF barriers is
choroidal cells which are joined with each other by tight
junctions forming the blood-CSF barrier (similar
permeability to BBB)
Highly lipid soluble drugs can easily cross the blood-CSF
Barrier but moderatly soluble & ionize drugs permeate
slowly.
Mechanism of drug transport is similar to CNS &CSF
but the Degree of uptake may vary significantly.
 B. PHYSIOLOGICAL
5) BARRIERS
Placenta
barriers
 B. PHYSIOLOGICAL BARRIERS
• 5) Placenta barriers ;-
• It’s the barrier b/w Maternal & Fetal blood vessels
• Both are separated by fetal trofoblast basement membrane &
endothelium .
• Thickness 25µ @ early pregnancy later reduce up to 2µ (even
its effectiveness remain unchanged)
• Mol wt <1000 Dalton & moderate to high lipid solubility drugs like…..
(Sulfonamides, Barbiturets, Steroids, Narcotic some Antibiotics ) cross
the barrier by Simple Diffusion rapidly
• Essential Nutrients for fetal growth transported by carrier-mediated
processes.
• Immunoglobulines are transported by endocytosis.
• Drugs dangerous to fetus at Two stages
• Its advisable to avoid drugs during 1st trimester
(fetal organ development) some drugs produce teratogenic effect

ex.
Phenytoin, methotrexate
 later stage pregnancy affect physiological functions like
 B. PHYSIOLOGICAL BARRIERS
6) Blood - Testis Barrier :-

This barrier not located @ capillary endothelium

level. But at sertoli - sertoli cell junction.

It is the tight junction / barrier b/w neighboring sertoli cells that act
as blood-testis barrier .

This barrier restrict the passage of drugs to spermatocytes

& spermatids.
 2). ORGAN TISSUE SIZEAND PERFUSION RATE
Perfusion Rate : - is defined as the volume of blood that flows per
unit time per unit volume of the tissue (ml/min/ml)
Perfusion rate - limited when…………………..
1) Drug is highly lipophilic
2)Membrane across which the drug is supposed to diffuse
Above both the cases Greater the blood flow , Faster the
distribution
□ Distribution is permeability rate - limited in following cases
 When the drug is ionic/polar/water soluble
 Where the highly selective physiology barrier restrict the
diffusion of such drugs to the inside of cell.

□ Distribution will be perfusion rate - limited

 When the drug is highly lipohilic
 When the membrane is highly permeable.

It is defined as the volume of the blood that flows per unit time per
unit volume of the tissue.
Unit: ml/min/ml

(Distribution Rate Constant) Kt = perfusion rate /

Kt/b Distribution half life = 0.693/Kt
=0.693Kt/b/perfusion rate
tissue/blood partition coefficient
Kt/b
 most selective barrier

Highly permeable capillary wall permits passage of almost

all drugs (except those bound to plasma protein).
Highly perfused tissues Lungs, Kidneys, Liver, Heart, Brain are
rapidly equlibriated with lipid soluble drugs
Drug is distributed in a particular tissue or organ depends upon
the
size of tissue (Volume) & Tissue/blood partition coefficient
Ex.Thiopental i.v (liphopillic drug) & high tissue/blood
partition coefficient towards brain & adipose tissue
But brain is highly perfused organ so drug is distributed fast
and shows rapid onset of action than poorly perfused adipose
tissue.
3) Binding of drug to blood and other tissue
components
• Binding of drugs to blood components
 3).BINDING OF DRUG TO TISSUE COMPONENTS
a) Binding of drug to blood components;-
i) Plasma protein bindings
• Human serum albumin:-all types drug

•ά 1- acid glycoprotein :-basic drugs(impr)

• Lipoproteins :-basic,lipophilic drugs(chlorpromazin)
•ά Globuline :-steroids like
1-

corticosterone ,vit- B12

•ά 2- Globuline :-vit-A,D,E,K,cupric ions.
• Hemoglobin :-Phenytoin, phenothiazines.
ii) Blood cells bindings:-
RBC : 40% of blood comprise of blood cells
out of that 95% cells are RBC (RBC comprise
of hemoglobin)
drugs like, phenytoin,phenobarbiton binds
The major component of blood is RBC
The RBC comprises of 3 components each of which can
bind to drugs:
 Hemoglobin
 Carbonic Anhydrase
 Cell Membrane
 BINDING OF DRUGS TO PLASMAPROTEINS
 The binding of drug to plasma protein is reversible

• The extent or order of binding of drugs to various plasma

proteins is:
Albumin >α1-Acid Glycoprotein> Lipoproteins > Globulins

Human Serum Albumin

 Most abundant plasma protein with large drug binding
capacity

 Both endogenous compounds and drugs bind to HSA

 Four different sites on HSA:

Site I: warfarin and azapropazone binding site
Site II: diazepam binding site
Site III: digitoxin binding
site Site IV: tamxifen
binding site
 3).BINDING OF DRUG TO TISSUE COMPONENTS
B. Extra Vascular Tissue proteins
• 40% of total body weight comprise of vascular
tissues
• Tissue-drug binding result in localization of drug at
specific site in body and serve as reservoir

• As binding increases it also increase bio-logical

half life.

• Irreversible binding leads to drug toxicity.

(carbamazepin-autoinduction)
• liver>kidney>lungs>muscle>skin>eye>bone>Hair,
nail
4). Miscellaneous Factors
 Age:
a)Total body water

b) Fat content

c) Skeletal muscles

d) Organ composition

e) Plasma protein
content
 Pregnancy

 Obesity

 Diet

 Disease states
a) AGE:-

4). MISCELLANEOUS FACTORS

Difference in distribution pattern is mainly due to
Total body water -(both ICF & ECF) greater in infants
Fat content - higher in infants & elderly
Skeletal muscle - lesser in infants & elderly
organ composition – BBB is poorly developed in infants & myelin
content is low & cerebral blood flow is high, hence greater
penetration of drug in brain
plasma protein content- low albumin in both infants & elderly
b) PREGNANCY:-
During Pregnancy, due to growth of UTERUS, PLECENTA, FETUS…
Increases the volume available for distribution drug.
fetus have separate compartment for drug distribution, plasma & ECF
Volume also increase but albumin content is low.
C) OBECITY : -
In obese persons, high adipose (fatty acid) tissue so high distribution of
lipophilic drugs
 4). MISCELLANEOUS FACTORS
d) DIET:- A diet high in fats will increases free fatty acid levels
circulation
in thereby affecting binding of acidic drugs (NSAIDs to
albumin)

e) DISEASE STATES:- mechanism involved in alteration of

drug distribution in disease states.
i) Altered albumin & other drug-binding protein
concentration.
ii) Alteration or reduced perfusion to organ or tissue
iii) Altered tissue pH.
iv) Alteration of permeability of physiological barrier (BBB)
EX- BBB(in meningitis & encephalities) BBBbecomes more
permeable polar antibiotics ampicilin, penicilin G. &
patient affect CCF, Perfusion rate to entire body decreases it
affect distribution.
f) DRUG INTERACTION:-Displacement interaction occurs when
two drugs administered which having similar binding site
affinity.
 Apparent Volume Of Distribution

Hypothetical vol. of body fluid into which a drug is dissolved or

distributed. The apparent volume of distribution is a
proportionality constant relating the plasma concentration to the
total amount of drug in the body.
XαC
X=Vd.C
Vd=X/C

Apparent volume amount of drug in the

= of body/ plasma drug
distribution concentration
Apparent volume of distribution is dependent on
concentration of drug in plasma.

Drugs with a large apparent volume are more concentrated

in extra vascular tissues and less concentrated
In certain pathological cases, the Vd for the drug may be altered
if the distribution of the drug is changed.

Vd=X/C
Vd=X0 /Co
=i.v.
bolu
s
dose/
conc
Vd(area)=X0/KE(AUC)
entra
tion
of
For drug
drugs administered extravascularly:
in Vd(area) = FXo/KE(AUC)
plas
ma
for drugs
given as