BP-604T.

BIOPHARMACEUTICS AND PHARMACOKENICTS (Theory)

UNIT-ONE (Part 2)

Prepared By-
Mr. Chandresh Maurya

UNIT-ONE Part -2 5 Horus

Distribution Tissue permeability of drug ,binding of

drug, apparent ,volume of drug distribution, plasma
and tissue protein binding ,kinetics of protein binding
clinical significances of protein binding of drugs
DRUG DISTRIBUTION IN THE BODY
Distribution: Distribution is the reversible transfer of a drug between one
compartment and other.
Since the process is carried out by the circulation of blood, one compartment
is always the blood or the plasma and the other represents extravascular
fluids and other body tissues

❖ Distribution of a drug is not uniform through out the body because

different tissues receive the drug form plasma at different rates and to
different extents
Tissue permeability of the drugs

➢ Physicochemical properties like molecular size, pKa and o/w partition

coefficient.
➢ Physiological barriers to diffusion of drugs.
Binding of drugs to tissue components

➢ Binding of drugs to blood components

➢ Binding of drugs to extravascular tissue proteins.
Miscellaneous factors

➢ Age
➢ Pregnancy
➢ Obesity
➢ Diet
➢ Disease states
➢ Drug interaction

➢ TISSUE PERMEABILITY OF DRUGS

Two major rate-determining steps in the distribution of drugs are:

✓ Rate of blood perfusion
✓ Rate of tissue permeability
If the blood perfusion to the tissues are high then the tissue permeability will be the
rate determining step in the processof distribution.
The tissue permeability of a drug depends upon the physicochemical properties of the
drug as well as the physiologicalbarriers.
 Physicochemical properties of the drugs:
➢ Molecular size
Almost all drugs having molecular weight less than 500 to 600 daltons easily
cross the capillary membrane to diffuseinto the extracellular fluid (ECF).

✓ Only small, water-soluble molecules and ions of size below 50 daltons enter
the cell through water channels.
✓ Larger molecules are transported through specialized transport system existing
on the cell membrane.
➢ Degree of ionisation Most drugs are either weak acids or weak bases and
their degree of ionization at plasma or ECF pH (i.e. 7.4) depends upon their
pKa.
All the drugs that ionize are plasma pH (i.e. polar hydrophilic drugs) cannot
penetrate the lipoidal cell membrane and tissue permeability is the rate
determining step

Physiological barriers to distribution of drugs

Some of the important simple and specialized physiologic barriers are:
➢ Simple capillary endothelial barrier
➢ Simple cell membrane barrier
➢ Blood-Brain-Barrier (BBB)
➢ Cerebro Spinal Fluid Barrier (CSF Barrier)
 ➢ Placental Barrier
➢ Blood-Testis Barrier

➢ The simple capillary endothelial barrier:

The membrane of capillary are unicellular in thickness; are practically no barrier for
drugs having molecular weight under 600 daltons. Only drugs bound to blood
components
e.g. plasma protein, blood corpuscles are restricted due to large molecular size of the
complex.

➢ The simple cell membrane barrier

Once a drug diffuses from the capillary wall into the extracellular fluid, its further
entry into cells of most tissues is limited by its permeability through the cell
membrane that lines such cells.
➢ Blood Brain Barrier
The brain capillaries consist of endothelial cells which are joined to one another
by continuous, tightly intercellular junctions comprising what is called as the
blood-brain-barrier.
the capillaries in the brain are highly specialized and much less permeable to
hydrophilic molecules. More over the glial cells and basement membrane forms a
solid envelope around the brain capillaries. As a result, the intercellular passage is
blocked and for a drug to gain access from the capillaries circulation into the brain,
it has to pass through cells rather than between them
✓ Since the BBB is a lipoidal barrier, it allows only the drugs having high Ko/w to
diffuse passively.
✓ Moderately lipid soluble and partially ionized molecules penetrate at a slow rate

➢ Blood-cerebrospinal barrier
The cerebro-spinal fluid (CSF) is formed mainly by the choroidal plexus of the
lateral, third and fourth ventricles and is similar in composition to the ECF of brain.

✓ A drug that enters the CSF slowly cannot achieve a high concentration as
the bulk flow of CSF continuously removes the drug.

➢ Placental barrier The human placental barrier has a mean thickness of 25 m in

early pregnancy that reduces to 2 m at full term. Many drugs having molecular
weight less than 1000 daltons and moderate to high lipid solubility

ORGAN/TISSUE SIZE AND PERFUSION RATE

Perfusion rate is defined as the volume of blood that flows per unit time per unit
volume of the tissue.
❖ It is expressedin ml (of blood)/min/ml (of the tissue).
Relative volume of different organs and tissues and their perfusion rates

Perfusion rate
Organ/Tissue %k of Body volume
(ml blood/min/ml of tissue)
I. Highly perfused tissue
1. Lungs 0.7 10.2
2. Kidneys 0.4 4.5
3. Adrenals 0.03 1.2
4. Liver 2.3 0.8
5. Heart 0.5 0.6
6. Brain 2.0 0.5
II. Moderately perfused tissue
7. Muscles 42.0 0.034
8. Skin 15.0 0.033
III. Poorly perfused
9. Fat (adipose tissue) 10.0 0.03
10. Bone (skeleton) 16.0 0.02
➢ Age
Differences in distribution pattern of a drug in different age groups are mainly
due to differences in –
✓ Total body water (both intracellular and extracellular) – is much greater in
infants.
✓ Fat content – is also higher in infants and elderly.
✓ Skeletal muscles – are lesser in infants and in elderly.
✓ Organ composition – the blood brain barrier is poorly developed in
infants, the myelin content is low and cerebralblood flow is high, hence
greater penetration of drugs in the brain.
✓ Plasma protein content – low albumin content in both infants and in elderly.

➢ Pregnancy
✓ During pregnancy, the growth of uterus, placenta and fetus increases the
volume available for distribution of drugs.
✓ The fetus represents a separate compartment in which a drug can
distribute. The plasma and the extracellular fluid volume also increase
but their is a fall in albumin content.

➢ Obesity
In obese persons, the high adipose tissue content can take up a large fraction of
lipophilic drugs despite the
fact that perfusion through it is low. The high fatty acid levels in obese
persons alter the binding characteristics ofacidic drugs.

➢ Diet
A diet high in fats will increase drugs such as NSAIDs to albumin.
➢ Disease states
A number of mechanisms may be involved in the alteration of drug
distribution characteristics in disease states

✓ Altered albumin and other drug-binding protein concentration

✓ Altered or reduced perfusion to organs or tissues
✓ Altered tissue pH.

xample: An interesting example of altered permeability of the physiologic

barrier is that of blood brain barrier (BBB). In meningitis and encephalitis,
the BBB becomes more permeable and thus polar antibiotics such as
penicillin G and ampicillin which do not normally cross it, gain access to the
brain.

Drug interactions
Drug interactions that affect distribution are mainly due to differences in
plasma protein or tissue binding of drugs
.
PROTEIN BINDING OF DRUGS
➢ Protein binding is define as the ability of protein to form bonds with other
substance such as blood components plasma , blood cell

➢ A drug in the body can interact with several tissue components of which the
two major categories are blood and extravascular tissues.
➢ The interacting molecules are generally the macromolecules such as proteins,
DNS and adipose tissue.
➢ The phenomenon of complex formation with proteins is called protein binding
of drugs.

➢ Protein-drug binding: Binding of drugs to various tissue components and its

influence on deposition and clinical response. Only the unbound drug moves
reversibly between the compartments.
Binding of drugs falls into two classes:

1. Binding of drugs to blood components like -

➢ Plasma proteins
➢ Blood cells
2. Binding of drugs to extravascular tissue proteins,

➢ fats,
➢ bones, etc
1. Binding of drugs to blood components

➢ Plasma Protein Binding

The extent or order of binding of drugs to various plasma proteins is:
albumin > 1Acid Glycoprotein > lipoproteins > globulins

Blood proteins to which drugs binds

Protein Molecular weight Concentration (g %) Drugs that bind
Human serum albumin large variety of all types of drugs
3.5 - 5.0
65,000
basic drugs such as imipramine,
1 - Acid glycoprotein 0.04 - 0.1
44,000 lidocaine, quinidine, etc.

basic, lipophilic drugs like

Lipoproteins variable
200,000 to 3,400,000 chlorpromazine

59,000 steroids like corticosterone, and

1- Globulin 0.003-0.007
thyroxine and cyanocobolamine
(Vit. B12)

134,000 vitamins A, D, E and K and

2- Globulin 0.015-0.060
cupric ions
64,000 Phenytoin, pentobarbital and
Hemoglobin 11-16
phenothiazines
 ➢ Binding of drugs to blood cells
More than 40% of the blood comprises of blood cells of which 95% is RBC. Thus
significant RBC binding ofdrug is possible. The RBC comprises of 3 components:
Haemoglobin: Phenytoin, pentobarbital and phenothiazines bind to haemoglobin.
Carbonic anhydrase :Acetazolamide and chlorthalidone (carbonic anhydrase
inhibitors)
Cell membranes :Imipramine and chlorpromazine are reported to bind to RBC
membrane

Binding of drugs to extravascular tissue proteins:

➢ Tissue binding of drugs

Tissue-drug binding is important from two point of views:
(i) It increase the volume of distribution (by reducing the concentration of free drug in
the plasma)
(ii) drug bound to tissue acts as a reservoir and hence biological half life increases.
➢ For majority of drugs that bind to extravascular tissues, the order of binding is :
liver > kidney > lung > muscle

Liver: Oxidation products of carbon tetrachloride and paracetamol bind irreversibly

with liver tissues resulting in hepatotoxicity.
Kidneys: Metallothionin, a protein present in the kidneys, binds to heavy metals
such as lead, mercury and cadmium.
.Lungs : Basic drugs like imipramine, chlorpromazine and antihistamines
accumulate in the lungs.
Bones : Tetracycline bind to bones and tee
Kinetics Of Protein-Drug Binding

Significance of protein binding

➢ Absorption
✓ From the absorption site the drug is absorbed to the blood. This absorption process
will stop when free drug concentration at both sides become equal.
✓ If the drug is bound significantly to plasma protein then free drug in the plasma
becomes less and hence the absorption process goes on. Thus much more amount of
drug is absorbed.
➢ Systemic solubility of drugs
✓ Water insoluble drugs, neutral endogenous macromolecules (such as heparin,
steroids and oil soluble vitamins) are circulated and distributed to tissues by
binding to lipoproteins.
➢ Distribution

✓ Some drug may bind to a specific tissue and may produce toxic reaction to the
tissue. Plasma protein binding restricts the entry of the drug into a tissue, thus saves
 the tissue.
✓ A protein bound drug does not cross the blood brain barrier, the placental barrier and
the glomerulus.
➢ Tissue binding, apparent volume of distribution and drug storage
✓ A drug that is extensively bound to blood components remains confined to blood
and very little amount of drug will be available for distribution in the tissues. In this
case the apparent volume of distribution (Vd) will be decreased.
✓ If the drug is bound to some tissue then the concentration of drug in the blood
compartment will be less hence the Vd will be high.
✓ In both the cases the drug-protein complex will act as drug reservoir

➢ Elimination
✓ Only the unbound or free drug can be eliminated because the drug-
protein complex cannot penetrate into the metabolising organ (e.g.
liver).
✓ The large molecular size of the complex prevents it from filtration
through glomerulus. Thus drugs which are more than 95% bound to
protein eliminates slowly and the elimination half life will be
➢ Displacement interaction and toxicity
✓ If two drugs A and B, both have the same binding sites to plasma
protein then one drug will displace the other.
✓ Thus the free drug concentration of both the drug in the plasma will rise
and may precipitate toxic reaction. e.g. warfarin and phenylbutazone.
➢ Diagnosis

✓ Thyroid gland (tissue) has great affinity for iodine. So any disorder of
thyroid gland can be detected by administering compounds with
radioactive iodine (I131)
➢ Therapy and drug targeting
The binding of drugs to lipoproteins can be used for site specific delivery of
hydrophilic moieties. e.g. in cancer therapy tumour cells have great affinity for
LDL (low density lipoprotein) than normal tissues. Hence binding of suitable
neoplastic agent to LDL can be used as a therapeutic tool.