DRUG DISTRIBUTION

PHA 2103
Dr.Taita Towett Lee (M.P.S., Bpharm., MUST)
OBJECTIVES
 Students should be able to;
Define drug distribution.
Discuss the factors affecting drug distribution.
Discuss some of the important physiological barriers to drug
distribution.

2
INTRODUCTION
 Drug distribution is the process by which a drug reversibly
leaves the bloodstream and enters the interstitium and then
the cells of the tissues.
 For a drug administered IV, when absorption is not a factor,
the initial phase represents the distribution phase, during
which a drug rapidly disappears from the circulation and
enters the tissues.
 This is followed by the elimination phase when drug in the
plasma is in equilibrium with drug in the tissues.

3
4
FACTORS AFFECTING DRUG DISTRIBUTION

1. Blood flow.
2. Capillary permeability.
3. Binding of drugs to plasma proteins and tissues.
4. Volume of distribution.

5
1. Blood flow
 The rate of blood flow to the tissue capillaries varies widely
as a result of the unequal distribution of cardiac output to
the various organs.
 Blood flow to the brain, liver, and kidney is greater than that
to the skeletal muscles.
 Adipose tissue, skin, and viscera have still lower rates of
blood flow.

6
2. Capillary permeability.
 Capillary permeability is determined by:
Capillary structure.
The chemical nature of the drug.
Capillary structure:
 Varies widely in terms of the fraction of the basement
membrane that is exposed by slit junctions between endothelial
cells.
 In the liver and spleen, a large part of the basement membrane is
exposed due to large, discontinuous capillaries through which
large plasma proteins can pass.
7
 In the brain the capillary structure is continuous and there are
no slit junctions.
 To enter the brain, drugs must pass through the endothelial
cells of the capillaries of the CNS or be actively transported.
 Lipid-soluble drugs readily penetrate into the CNS because
they can dissolve in the membrane of the endothelial cells
(blood brain barrier).
 Ionized or polar drugs generally fail to enter the CNS because
they are unable to pass through the endothelial cells of the
CNS (blood brain barrier) which have no slit junctions.

8
9
3. Protein Drug binding
 Binding of drugs to plasma proteins:
Albumin, α1-acid glycoprotein, lipoproteins, globulins.

 Binding of drugs to RBCs.

10
(a) Binding to plasma proteins
 Following entry of the drug into systemic circulation, the first
thing with which it can interact is blood components like plasma
proteins, blood cells and haemoglobin.
 The main interaction of the drug in blood compartment is with
plasma proteins which are present in abundant amounts and in
large variety.
 The binding of drugs to plasma proteins is reversible.
 Plasma proteins include: Albumin, α1-acid glycoprotein,
lipoproteins and globulins.

11
 The order of binding of drugs to plasma proteins is Albumin >
α1-acid glycoprotein > lipoproteins > globulins.

12
(i) The human serum albumin (HSA):
 Most abundant plasma protein.
 Has a molecular weight of 65000 with a large drug binding
capacity.
 Binds several drugs with varied structures both endogenous
(fatty acids, bilirubin, tryptophan) and drugs (weak acids, neutral
and weak bases).
 Has four sites for drug binding; I, II, III and IV; drugs majorly bind
to site I and II.
 Examples of drugs that bind HSA include: phenylbutazone,
indomethacin, sulphonamines, benzodiazipines etc.
13
(ii) Binding of drugs to α1-acid glycoprotein (AAG or α1-
AGP):
 Has a molecular weight of 44,000.
 Also called orosomucoid.
 It binds a number of basic drugs like amitriptyline, imipramine,
nortriptyline, lidocaine, propranolol, quinidine and disopyramine.

(iii) Binding of drugs to lipoproteins:

 Binding involves dissolution of the drug in the lipid core of the
lipoprotein.

14
 Lipid core contains triglycerides, cholesteryl esters and the
outside is made of apolipoproteins.
 Plasma lipoproteins include: Chylomicrons, VLDL, LDL and
HDL.
 A number of basic (e.g. chlorpromazine), neutral (e.g.
cyclosporine A) and acidic (e.g. diclofenac) drugs bind to
lipoproteins.
 Basic, lipophilic drugs have relatively more affinity.
 Lipoprotein binding becomes significant in cases of drugs that
predominantly bind to them and when the levels of HSA and
AAG in plasma are decreased.
15
(IV) Binding of drugs to globulins:
 Several globulins have been identified and are labelled as α1-, α2-,
β1-, β2-, and γ- globulins.
 α1-globulin (transcortin or corticosteroid binding globulin,
CBG) binds a number of steroid drugs such as cortisone and
prednisolone. It also binds thyroxine and cyanocobalamin.
 α2-globulin (ceruloplasmin) binds fat soluble vitamins (ADEK)
and cupric ions.
 β1-globulin (transferrin) binds ferrous ions.
 β2-globulin binds carotenoids.
 γ-globulins binds specifically to antigens
16
Binding of drugs to Red blood cells
 The RBCs constitute 95% of total blood cells.
 The RBC comprises 3 components each of which can bind
drugs:
a) Hemoglobin:
Has molecular weight of 64,500 (almost equal to that of
HSA) but is 7-8 times the concentration of albumin in blood.
Binds drugs like phenobarbital, phenytoin and
phenothiazines.
17
b) Carbonic anhydrases:
 Drugs known to bind it are acetazolamide and chlorthalidone
(i.e. carbonic anhydrase inhibitors).

c) Cell membrane:
 Imipramine and chlorpromazine bind RBC membrane.

18
Binding to tissue proteins
 Numerous drugs accumulate in tissues, leading to higher
concentrations of the drug in tissues than in the extracellular
fluids and blood.
 Drugs may accumulate as a result of binding to lipids, proteins
or nucleic acids.
 Drugs may also be actively transported into tissues.
 These tissue reservoirs may serve as a major source of the drug
and prolong its actions or, on the other hand, can cause local
drug toxicity

19
 In contrast to plasma protein binding, a number of drugs
irreversibly bind to tissues e.g. oxidation products of
paracetamol bind covalently to hepatic tissues.
 Factors influencing localization of drugs to tissues include:
Lipophilicity and structural features of the drug.
Perfusion rate.
pH differences.
 Extensive tissue drug binding suggests that a tissue can act as
the storage site for drugs.
 For majority of drugs that bind extravascular tissues, the order
of tissue binding is liver > Kidney > lung > muscle.
20
 Examples of extravascular drug-tissue binding are:

i. Kidneys:
 Metallothionein, a protein present in the kidneys binds to heavy
metals such as lead, mercury and cadmium and results in their
accumulation and toxicity.
 Acrolein, a metabolite of cyclophosphamide (anticancer)
accumulates in renal cells and cause toxicity.

ii. Liver:
 Paracetamol irreversibly binds to liver tissues resulting in
hepatoxicity.
21
iii. Lungs:
 Basic drugs like imipramine, chlorpromazine and antihistamines
accumulate in the lungs.

iv. Skin:
 Chloroquine and phenothiazines accumulates in the skin by
interacting with melanin.

v. Eyes:
 Retinal pigments of the eye also contain melanin. Binding of
chloroquine and phenothiazines to it is responsible for retinopathy.
22
vi. Bones:
 Tetracycline is a well known example of a drug that binds to bone
and teeth.

vii. Fat:
 Lipophilic drugs such as thiopental and pesticide DDT accumulate in
the adipose tissue by partitioning into it.

23
4.Volume of distribution
Apparent volume of distribution:
 The volume of plasma into which the total amount of the drug
in the body would be required to be dissolved in order to
reflect the drug concentration attained in plasma.
 It is calculated by dividing the dose that ultimately gets into the
systemic circulation by the plasma concentration at time zero
(C0).
𝐴𝑚𝑜𝑢𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦
Vd=
𝐶𝑜

24
 Although Vd has no physiologic or physical basis, it can be
useful to compare the distribution of a drug with the volumes
of the water compartments in the body.

25
Drug distribution into the water compartments in
the body.
 Once a drug enters the body, from whatever route of
administration, it has the potential to distribute into any one of
three functionally distinct compartments of body water.

I. Plasma compartment:
 If a drug has a very large molecular weight or binds
extensively to plasma proteins, it is too large to move
out through the endothelial slit junctions of the capillaries
and, thus, is effectively trapped within the plasma (vascular)
compartment.
26
 As a consequence, the drug distributes in a volume (the
plasma) that is about 6% of the body weight or, in a 70-kg
individual, about 4L of body fluid. Heparin (anticoagulant)
shows this type of distribution.

27
II. Extracellular fluid:
 If a drug has a low molecular weight but is hydrophilic, it can
move through the endothelial slit junctions of the capillaries
into the interstitial fluid.
 However, hydrophilic drugs cannot move across the lipid
membranes of cells to enter the water phase inside the cell.
 These drugs distribute into a volume that is the sum of the
plasma water and the interstitial fluid, which together
constitute the extracellular fluid.
 This is about 20% of the body weight, or about 14L in a 70-kg
individual.
 Aminoglycoside antibiotics e.g. gentamicin show this type of
distribution.
28
III. Total body water:
 If a drug has a low molecular weight and is hydrophobic, it can
move into the interstitium through the slit junctions and into the
intracellular fluid through the cell membranes.
 The drug, therefore, distributes into a volume of about 60% of
body weight, or about 42L in a 70-kg individual.
 Ethanol exhibits this apparent volume of distribution.

29
Apparent volume of distribution
 A drug rarely associates exclusively with only one of the
water compartments of the body.
 The vast majority of drugs distribute into several
compartments, often avidly binding cellular components e.g.
lipids (abundant in adipocytes and cell membranes), proteins
(abundant in plasma and within cells), and nucleic acids
(abundant in the nuclei of cells).
 The volume into which drugs distribute is called the apparent
volume of distribution (Vd).
 Vd is a useful pharmacokinetic parameter for calculating a
drug’s loading dose.
30
Determination of Vd
 The fact that drug clearance is usually a first order process
(constant fraction of the drug is eliminated per unit of time)
allows calculation of Vd.
 This process can be analysed by plotting the log of the plasma
drug concentration (Cp) versus time.
 The concentration of drug in the plasma can be extrapolated
back to time zero (the time of injection) on the Y axis to
determine C0, which is the concentration of drug that would have
been achieved if the distribution phase had occurred instantly.
 This allows calculation of Vd as:
𝐷𝑜𝑠𝑒
 Vd=
𝐶𝑜
31
Note:
1. Drugs which bind selectively to plasma proteins or other
blood components e.g. warfarin have low Vd i.e. the drug is
poorly distributed and mainly in plasma.
2. Drugs which bind selectively to extravascular tissues have
large Vd i.e. the drug is highly distributed in tissues.
3. Factors that produce an alteration in binding of the drug to
blood components result in increase in Vd and those that
influence drug binding to extravascular components result in
decrease in Vd.

32
4. A large Vd has an important influence on the half-life of a drug,
because drug elimination depends on the amount of drug
delivered to the liver or kidney or other organs where
metabolism occurs per unit of time.
5. If the Vd for a drug is large, most of the drug is in the
extraplasmic space and is unavailable to the excretory organs.
6. Therefore, any factor that increases Vd can lead to an increase
in the half-life and extend the duration of action of the drug

33
Physiological Barriers to Distribution of
Drugs.
 A membrane (barrier) with special structural features can be
a permeability restriction to the distribution of drugs to
some tissues.
 Some important physiological barriers are:
i. Blood-brain barrier.
ii. Placental barrier.
iii. Blood-testis barrier.

34
i. Blood Brain Barrier:
 Unlike capillaries found in other body parts, the capillaries in the
brain are highly specialized and much less permeable to water
soluble drugs.
 The brain capillaries consist of endothelial cells which are joined
to one another by continuous tight intercellular junctions
comprising what is called the blood brain barrier.

Blood brain barrier

35
 The presence of special cells called astrocytes which are special
elements of the supporting tissue found at the base of the
endothelial membrane form a sloid envelope around the brain
capillaries.
 As a result, the intercellular passage is blocked and for a dug to
gain access from the capillary circulation into the brain, it has to
pass through the cells rather than between them.
 Since the BBB is a lipoidal barrier, it allows only the drugs having
high oil/water (o/w) partition coefficient to diffuse passively
whereas moderately lipid soluble and partially ionized molecules
penetrate at a slow rate.

36
ii. Placental Barrier:

 The maternal and fetal blood vessels are separated by a number

of tissue layers made of fetal trophoblast basement membrane
and the endothelium which together constitute the placental
barrier.
37
 Many drugs having molecular weight less than 100 daltons and
moderate to high lipid solubility e.g. ethanol, sulphonamides
and steroids cross the placental barrier by simple diffusion
quite rapidly.
 Generally, lipid soluble drugs cross the placental barrier more
easily than polar drugs.

iii. Testis Blood Barrier:

 This barrier is not located at capillary endothelium level but at
sertoli-sertoli cell junction.
38
 It is the tight junctions between the neighboring sertoli cells
that act as the blood-testis barrier.
 This barrier restricts the movement of drugs to
spermatocytes and spermatids.

39
THE END

40