This document discusses drug distribution, which refers to the reversible transfer of drugs between compartments, primarily between blood and extravascular tissues. It describes the steps in drug distribution, from permeation of blood vessels into interstitial fluid and intracellular fluid. Factors that affect distribution include tissue permeability, organ perfusion rates, protein binding, and physiological barriers like the blood-brain barrier. Methods for studying distribution patterns include using specific tracers to measure fluid compartment volumes and microdialysis to sample extracellular fluids.

1. DISTRIBUTION OF
DRUGS
B I O P H A R M A C E U T I C S | | P H A R M A C O L O G Y
B Y A L O Y S I A C A R D O S O
D E P T O F P H A R M A C E U T I C S ( M . P H A R M )

2. INDEX
• What Is Disposition?
• What Is Distribution?
• Steps In Drug Distribution
• Factors Affecting Distribution Of Drugs
• Physiological Barriers To Distribution
• Volume Of Distribution
• Specific Tracers Or Markers
• Methods For Studying Drug Distribution Pattern

3. WHAT IS DISPOSITION
• DISPOSITION is a process that tends to lower the plasma concentration in the blood
• Two major process:
1)Distribution
Involves reversible transfer of drugs between compartment
2)Elimination
Irreversible loss of drug from the body
Further divided into 2 process
1. Biotransformation
2. Excretion

4. • Distribution is defined as reversible transfer of a drug between one
compartment to another
• One compartment is always blood or the plasma
• Other is extravascular fluids and other body tissues
Other words ,Distribution is reversible transfer of a drug between the
blood and extravascular fluids and tissue.
• Distribution is passive process
• Driving force is concentration gradient between blood &extravascular
fluids and tissue.

5. DISTRIBUTION
Steps in drug distribution
(Systemic circulation to extravascular tissue)
1.Permeation of free or unbound drug
Blood(capillary wall) interstitial/extracellular fluid(ECF)
2.Permeation of drug (ECF):
Memberane of tissue cell intracellular fluid
a)Rate of perfusion to extravascular tissue
b)Membrane permeability of drug.

6. FACTORS AFFECTING DISTRIBUTION OF DRUGS
1. Tissue permeability of the drug
• Physiochemical properties of the drug like molecular size,pka,&o/w partition
coefficient
• Physiological barriers to diffusion of drugs
2.organ/tissue size &perfusion rate
3.Binding of drugs to tissue components
• to blood components
• Binding of drugs to extravascular tissue proteins
4.Miscellaeous factor
1. Age
2. Pregnancy
3. Obesity
4. Diet
5. Disease state
6. Drug interaction

7. TISSUE PERMEABILITY OF DRUGS
Rate determining steps
• Rate of tissue permeation
• Rate of blood perfusion
If blood flow to entire tissues were rapid uniform diff in degree of distribution between
tissues will be indicative of diff in tissue permeability& process will be tissue permeation
rate limited.
• Tissue permeability depends 1)physiochemical properties of drug
2)physiological barriers
PHYSIOCHEMICAL PROPERTIES OF DRUG
• Properties of drugs that influence-molecular size, degree of ionistaion,partition
coefficient &stereo chemical nature.
Molecular weight(MW)
• Almost all drugs MW less than 500-600 Daltons(cross capillary memberaneextracellular
interstitial fluid)
• Penetration of drugs from ECFcell(depends on molecular size, ionisation constant, lipophilicity
of drug)
• Only small water-soluble molecules &ion size <50 Daltons enter the cell through aqueous filled

8. Degree of ionisation(pKa) & partition coefficient(Ko/w)
• Determine tissue permeability(imp factor)
• Most drugs are either weak acids or weak bases
• Degree of ionisation at plasma or ECF depends on pKa
• All drugs that ionise at plasma pH(polar, hydrophilic drugs)cannot penetrate the
lipoidal cell membrane & tissue permeability is rate limiting step in distribution of
such drugs.
• Only unionised which are generally lipophilic, rapidly cross the cell membrane
• Among drugs that have same o/w partition coefficient but differ in extent of
at blood pH,one that ionises to larger extent e.g. phenobarbital & salicylic acid,
phenobarbital is more ionised at blood pH & hence distributes rapidly.

9. • Thiopental, a non polar, lipophilic drug, largely unionised at plasma pH,readily
diffuses into the brain while penicillin which are polar, water soluble& ionised at
plasma pH do not cross BBB.
• Alteration of blood pH affect drug in unionised form distribution
1. Acidosis-decreased ionisation of acidic drugs, increased intracellular drug conc
&pharmacological action, favours extracellular distribution.
2. Alkalosis-opp effect.eg NAHCO3 induced alkalosis used in treatment of
barbiturates poisoning to drive the drug out &prevent further entry into CNS &
promotes urinary excretion by favoured ionisation, favours intracellular distribution.

10. PHYSIOLOGICAL BARRIERS TO DISTRIBUTION
• A membrane or a barrier with special structural features can be a
permeability restriction to distribution of drugs to some tissue.
1. Simple capillary endothelial barrier
2. Simple cell membrane barrier
3. Blood-brain barrier
4. Blood-CSF barrier
5. Blood-placental barrier
6. Blood-testis barrier

11. THE SIMPLE CAPILLARY ENDOTHELIAL BARRIER
1. All drugs, ionised or unionised with a molecular size less than 600 Daltons,
diffuse through the capillary endothelium and into interstitial fluid.
2. Only drugs bound to the blood components are restricted because of the
large molecular size of the complex

12. The simple cell membrane barrier
Once a drug diffuses from the capillary wall ECFcells of most tissues(limited by its
permeability through membrane that line such cells)

13. Blood brain barrier
• Capillaries in the brain are highly specialised & much less permeable to water soluble
drugs.
• The capillaries consist which are joined to one another by continuous tight
comprising what is called as the blood brain barrier.

14. • Morever,the presence of special cells called as pericytes & astrocytes, which are the
elements of the supporting tissue found at the base of endothelial membrane, form an
solid envelope around the brain capillaries.
• The intercellular(par acellular)passage is blocked & for a drug to gain access from the
capillary circulation into the brain, it has to pass through the cells(transcellular) rather
than between them.
• However, there are specific sites in the brain where the BBB does not exist, namely the
trigger area & median hypothalamus eminence.
Most drugs administered intranasal may diffuse directly into the CNS because of
continuity between submucosal areas of the nose & subarachnoid space of the olfactory
level. There is virtual absence of pinocytosis in brain.

15. • A solute may gain access to brain via one of the two pathways:
1. Passive diffusion through lipoidal barrier: which is restricted to small molecules(MW<700
Daltons)&high o/w partition coefficient.
2. Active transport of essential nutrients such as sugars & amino acids. Thus structurally similar
foreign molecules can also penetrate the BBB.
The effective Ko/w of thiopental, a highly soluble drug is 50 times that of phenobarbital &
crosses the BBB much more rapidly.
Most antibiotics which are polar such as penicillin ,water soluble & ionised at plasma pH,do not
cross the BBB under normal circumstances.
Selective permeability of lipid soluble moieties through the BBB makes appropriate choice of a
drug to treat CNS disorder part of therapy for e.g. Parkinsonism(depletion of dopamine in the
brain),can be treated by administration of dopamine as it doesn’t cross theBBB.Hence,levodopa
which can penetrate the CNS where it is metabolised to Dopamine used in treatment.

16. Approaches to promote crossing BBB
1. Use of permeation chancers such a DMSO(dimethyl sulphoxide)
2. Osmotic disruption of the BBB by infusing internal carotid artery with mannitol.
3. Use of Dihydropyridine redox system as drug carriers to the brain
Lipid soluble Dihydropyridine-carrier to polar drug to form a prodrug that readily
the BBB.in,the brain, the CNS enzyme oxidize the dihydropyridine moiety to the polar
pyridium ion from that cannot diffuse back out of the brain.as a result the drug gets
trapped I the cns.such a redox system used to deliver steroidal drugs to the brain.

17. BLOOD-CEREBROSPINAL FLUID BARRIER
• The cerebrospinal fluid (CSF) is formed mainly by the choroid plexus of a lateral, third
and fourth ventricles and is similar in composition to the ECF of brain.
• The capillary endothelium that lines the choroid plexus have open junctions or gaps
and drugs can flow freely into the extracellular space between the capillary wall and
the choroidal cells.
• However, the choroidal cells are joined to each other by tight junctions forming the
blood-CSF barrier which has permeability characteristics similar to that of the BBB.
• As In the case of BBB, only highly lipid soluble drugs can cross the blood –CSF barrier
with relative ease whereas moderately lipid soluble and partially ionised drugs
permeate slowly.

19. • A drug that enters the CSF slowly cannot achieve a high concentration as the bulk
flow of CSF continuously removes the drug.
• For any given drug, its concentration in the brain will always be higher than in the
CSF.
• Although the mechanisms for diffusion of drugs into the CNS and CSF are similar, the
degree of uptake may vary significantly. In some cases,
• CSF drug concentration may be higher than its cerebral concentration e.g.
sulphamethoxazole and trimethoprim, and vice versa in other cases, e.g. certain B-
blockers.

20. BLOOD PLACENTAL BARRIER
• The maternal and foetal blood vessels are separated by a number of tissue layers made
of foetal trophoblast basement membrane and the endothelium which together
constitute the placental barrier.
• The human placental barrier has a mean thickness of 25 microns(early pregnancy)&2
microns(full term)
• Drugs(MW<1000 Daltons) & moderate to high lipid solubility
eg.ethanol,sulphonamides,barbiturates,GA,steroids,narcotic
analgesics,anticonvulsants,antibiotics cross
by simple diffusion rapidly.
• Nutrients essential for foetal-carrier mediated transport.
• Immunoglobins-Endocytosis.

21. TETRAGON-An agent that causes toxic effect on foetus.
TETRAGONECITY-Foetal abnormalities caused by administration of drugs
during pregnancy

22. BLOOD TESTIS BARRIER
• Located at sertoli-sertoli cell junction.
• Tight junctions between the neighbouring sertoli cells that act as
blood testis barrier.
• Restricts passage of drugs to spermatocytes and spermatid

23. ORGAN/TISSUE SIZE &PERFUSION RATE
Perfusion rate is defined as the volume of blood that flows per unit time per unit
volume of tissue. Expressed in ml/min/ml of the tissue.
• If Kt/b is the tissue/blood partition coefficient of drugs then 1st order distribution
constant
Kb=perfusion rate
Kt/b
Permeability refers to the ease with which molecules cross biological membranes. It
may also refer to the ease with which ions or molecules pass through the pore of
channel proteins.

24. Permeability is rate limited in the following case
1)If Drug-ionic, polar or water soluble
2)Where, Highly selective physiological barrier
restrict diffusion of drug into the cell.
• Perfusion is rate limited
1)Drug is highly lipophilic
2)Membrane across the drug is supposed to diffuse is highly permeable such as those
capillaries & muscles.
• Greater the blood flow faster is the diffusion

25. • Extent of drug distribution depends on:
1. Size of the tissue
2. Tissue/blood partition coefficient(lipophilic drugs –high-brain & higher-
adipose tissue)
For thiopental,
Brain(high perfused organ)-rapid distribution
Adipose tissue(poorly perfused)-slow distribution
But
Adipose tissue(higher in volume)-greater affinity for the drug & approaches
equilibrium.

26. MISCELLANOUS FACTORS AFFECTING DRUG DISTRIBUTION
1. AGE
2. PREGNANCY
3. OBESITY
4. DIET
5. DISEASE STATE
6. DRUG INTERACTION

27. AGE
• According to age groups
1. Total body water(both extracellular &intracellular):greater in infants
2. Fat content: higher in infants & elderly.
3. Skeletal muscles: lesser (infants &elderly)
4. Organ composition:BBB(poorly developed in infants),
myelin content(low) ,cerebral blood flow(high).greater penetration of drugs in
infants.
5. Plasma protein content: low albumin content(infants& elderly)

28. PREGNANCY
VOLUME OF DISTIBUTION INCREASES(growth of uterus
&placenta increases)
Plasma & ECF volume increases
Albumin content decreases.
OBESITY
Obese person-high adipose tissue content-increased lipophilic
drug distribution.
Perfusion –low
High fatty acid levels-binding character of acidic drug increases

29. DISEASE STATE
• Altered -tissue pH,albumin &drug-binding
protein concentration.
• Reduced –Perfusion to organs or tissue.
• Altered –permeabilty.In meningitis& encephalitis,(BBB becomes more
permeable).hence polar antibiotics such as penicillin G &ampicillin which usually don’t
cross, gains entry into the brain.
DRUG INTERACTION
A drug interaction is a reaction between two (or more) drugs or between a drug and a
food, beverage, or supplement. Taking a drug while having certain medical conditions
can also cause a drug interaction. ... A drug interaction can affect how a drug works or
cause unwanted side effects

30. VOLUME OF DISTRIBUTION
The volume of distribution (VD, also known as apparent volume of distribution,
literally, volume of dilution) is the theoretical volume that would be necessary to
the total amount of an administered drug at the same concentration that it is observed
in the blood plasma.
In other words, It is the ratio of amount of drug in a body (dose) to concentration of
drug that is measured in blood, plasma, and un-bound in interstitial fluid.[
• The volume of distribution is given by the following equation
Vd=X/C
X=amount of drug in the body
C=plasma drug concentration

31. • Therefore, the dose required to give a certain plasma concentration can be determined
if the VD for that drug is known. The VD is not a physiologic value; it is more a
reflection of how a drug will distribute throughout the body depending on several
physicochemical properties, e.g. solubility, charge, size, etc.
• The unit for Volume of Distribution is typically reported in litres. As body composition
changes with age, VD decreases.
• Where:
• VP = plasma volume
• VT = apparent tissue volume
• fu = fraction unbound in plasma
• fuT = fraction unbound in tissue

32. SPECIFIC TRACERS OR MARKERS
The tracers used in medicine are complex organic molecules specifically chosen for
their affinity for the organ under examination. These molecules are 'marked' by the
presence of a radioactive nucleus, and are often injected intravenously.
The volume of each physiological compartment can be determined by use of specific
tracers or markers.
The plasma volume can be determined by use of substances of high molecular weight
substance that totally bound to plasma albumin, for eg.high molecular weight dyes
as Evans blue,indocyanine green and I-131 albumin.
.

33. PHYSIOLOGICAL FLUID
COMPARTMENT
MARKERS USED
PLASMA EVANS BLUE,INDOCYANINE GREEN,
I-131,ALBUMIN
ERYTHROCYTE CR-51
EXTRACELLULAR FLUID NON-METABOLISABLE
LIKE RAFFINOSE,INULIN,MANNITOL
RADIOISOTOPES OF SELECTED
IONS:Na+,Cl¯,Br¯,SO42-
TOTAL BODY WATER DUETERIUM OXIDE,ANTIPYRINE.

34. When given i.v they remain confined to the plasma.The ECF(extracellular fluid
volume)can be determined by substances that easily penetrate the capillary
membrane and distribute throughout the ECF but do not cross the cell membrane
e.g.Na+,Cl¯,Br¯,SCN¯ & SO42-
ions and inulin,mannitol & raffinose
Total body water (TBW) volume can be determined by use of substances that
distribute equally in all water compartments of the body (both intra- and
extracellular) for e.g. heavy water (D20). Tritiated water (HTO) and lipid soluble
substances such as antipyrine . The intracellular fluid volume is determined as the
difference between the TBW and ECF volume. The intracellular fluid volume including
those of blood cells is approximately 27 litres.

35. METHODS FOR STUDYING DRUG DISTRIBUTION PATTERN
• MICRODIALYSIS
This technique involves insertion of very fine probes into the tissues of the living body, mostly
fluids spaces, such as the CSF, and other extracellular fluids where possible.
The probes consist of at least two concentric tubes, and asemipermeable membrane separating
them, positioned such that an artificial dialysis fluid can be slowly infused through the probe and
past the membrane.
Unbound drug molecules in the tissues surrounding the probe diffuse into the flowing dialysate,
which is then collected for analysis. The limitation of this is its invasive nature.

36. MATRIX-ASSISTED LASER SESORPTION IONIZATION-MASS SPECTROMETRY
IMAGING(MALDI-MSI)
It is used to study drug localization within micro environmental tissue compartments.
Thin sections of animal tissues are exposed to pharmaceutical drugs by either spotting
submerging. MALDI-MSI is then performed on the tissue to localize drug-distribution
patterns

37. • AUTORADIOGRAPHY
In this approach, the radioactively labelled drug substanceunder investigation is
administered to test animals,usually mice or rats, which are killed at suitable time
intervals,and frozen sections of tissues or of the whole body prepared.
An image of the radiation is obtained by placing the sections next to a photographic
emulsion. Thus, if a whole body section is used, and the radioactivity is specifically
localized in highly perfused organs such as the lungs and liver. The image will reveal
Comparison with a normal photograph of the slice is used to identify which tissue
contain the radioactivity. Densitometry can be used to qualify the relative amounts of
radioactivity. This technique has been used to show highly-specific localization of drugs
in tissues.

38. POSITRON-EMISSION TOMOGRAPHY(PET)
Synthetic radioactive isotopes (e.g.) with atomic masses less than the
naturally occurring stable isotopes have half-life values of 2-110 minutes
and emit positrons that interact with electrons to emit gamma radiation
that can be detected outside the body.
The isotopes are generated in a cyclotron and incorporated into the drug molecules
immediately before the administrative of the drug. PET scanning permits the
of images of live organisms including humans.

39. REFERENCE
• D M Brahmankar and Sunil B.Jaiswal Biopharmaceutics and Pharmacokinetics A
Treatise.: Vallabh Prakashan; 2015.

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