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DRUG DISTRIBUTION

INTRODUCTION
Distribution
Pharmacokinetics is a Greek word and kinesis means movement. It is the study of the action
of drug in the body over a period of time, including the processes of liberation, absorption,
distribution, biotransformation and excretion(LADME). Distribution in pharmacology is a
branch of pharmacokinetics describing reversible transfer of drug from one location to
another within the body.

Pharmacokinetic
s

Liberation Absorption Distribution Metabolism Excretion

Drug distribution refers to the movement of drug to and from the blood and various tissues of
the body (for example, fat, muscle, and brain tissue) and the relative proportions of drug in
the tissues.

After a drug is absorbed into the bloodstream, it rapidly circulates through the body; the
average circulation time of blood is 1 minute. As the blood recirculates, the drug moves from
the bloodstream into the body's tissues.

Once absorbed, most drugs do not spread evenly throughout the body. Drugs that dissolve in
water (water-soluble drugs), such as the antihypertensive drug atenolol Some Trade Names
TENORMIN, tend to stay within the blood and the fluid that surrounds cells (interstitial
space). Drugs that dissolve in fat (fat-soluble drugs), such as the anesthetic drug halothane,
tend to concentrate in fatty tissues. Other drugs concentrate mainly in only one small part of
the body (for example, iodine concentrates mainly in the thyroid gland), because the tissues
there have a special attraction for and ability to retain (affinity) the drug.

Drugs penetrate different tissues at different speeds, depending on the drug's ability to cross
membranes. For example, the anesthetic thiopental Some Trade Names PENTOTHAL, a
highly fat-soluble drug, rapidly enters the brain, but the antibiotic penicillin, a water-soluble
drug, does not. In general, fat-soluble drugs can cross cell membranes more quickly than
water-soluble drugs can. For some drugs, transport mechanisms aid movement into or out of
the tissues.

Some drugs leave the bloodstream very slowly, because they bind tightly to proteins
circulating in the blood. Others quickly leave the bloodstream and enter other tissues, because
they are less tightly bound to blood proteins. Some or virtually all molecules of a drug in the
blood may be bound to blood proteins. The protein-bound part is generally inactive. As
unbound drug is distributed to tissues and its level in the bloodstream decreases, blood
proteins gradually release the drug bound to them. Thus, the bound drug in the bloodstream
may act as a reservoir for the drug.

Some drugs accumulate in certain tissues, which can also act as reservoirs of extra drug.
These tissues slowly release the drug into the bloodstream, keeping blood levels of the drug
from decreasing rapidly and thereby prolonging the effect of the drug. Some drugs, such as

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DRUG DISTRIBUTION

those that accumulate in fatty tissues, leave the tissues so slowly that they circulate in the
bloodstream for days after a person has stopped taking the drug.

Distribution of a given drug may also vary from person to person. For instance, obese people
may store large amounts of fat-soluble drugs, whereas very thin people may store relatively
little. Older people, even when thin, may store large amounts of fat-soluble drugs because the
proportion of body fat increases with age.1

The bloodstream carries drugs from the site of absorption to the target site and also to sites of
metabolism or excretion, such as the liver, kidneys, and, in some cases, the lungs. Many
drugs are bound to plasma proteins, and in some cases more than 90 percent of the drug
present in the plasma is bound in this way. This bound fraction is inert. Protein binding
reduces the overall potency of a drug and provides a reservoir to maintain the level of the
active drug in blood plasma. To pass from the bloodstream to the target site, drug molecules
must cross the walls of blood capillaries. This occurs rapidly in most regions of the body. The
capillary walls of the brain and spinal cord, however, are relatively impermeable, and in
general only drugs that are highly lipid-soluble enter the brain in any appreciable
concentration.2

Once a drug has gained access to the blood stream it gets distributed to other tissues that
initially had no drug. So, concentration gradient being in the direction of plasma to tissues.
The extent of distribution of a drug depends on its lipid solubility, ionization at physiological
pH, extent of binding to plasma and tissue proteins and difference in regional blood flow.
Movement of drug proceeds until an equilibrium is established between unbound drug in
plasma and tissue fluids. Subsequently there is a parallel decline in both due to elimination.*

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DRUG DISTRIBUTION

DESCRIPTION
The volume of distribution
The volume of distribution of a drug is property that quantifies the extent of distribution. By
the process of distribution a drug diffuses or is transferred from intravascular space to
extravascular space (body tissues). These spaces are described mathematically as volume(s)
of distribution.

In the simplest of terms, a drug's volume of distribution is that volume of bodily fluid into
which a drug dose is dissolved. Therefore, if we know the dose that was given, and we can
measure the serum level (concentration), then we can calculate a volume:

Volume of distribution (Vd) = Dose / drug

Of course, the human body is not a glass beaker. Drug is distributing in and out of many
tissue compartments while it is simultaneously being eliminated.3 Since the drug does not
actually distribute into 20 L of body water, with the exclusion of the rest of it this is only an
apparent volume of distribution which can be defined as the volume that would accommodate
all the drug in the body, if the concentration through out was the same as in plasma.*

Volume of distribution may be increased by renal failure (due to fluid retention) and liver
failure (due to altered body fluid and plasma protein binding). Conversely it may be
decreased in dehydration. The initial volume of distribution describes blood concentrations
prior to attaining the apparent volume of distribution and uses the same formula.

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 real volume; 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 units for Volume of Distribution are typically reported in (ml, liter, or liter)/kg body
weight. The fact that VD is a ratio of a theoretical volume to a fixed unit of body weight
explains why the VD for children is typically higher than that for adults, even though children
are smaller and weigh less. As body composition changes with age, VD decreases.4

Factors affecting volume of distribution

Blood Flow
The rate at which a drug reaches different organs and tissues will depend on the blood flow to
those regions. Equilibration is rapidly achieved with heart, lungs, liver, kidneys and brain
where blood flow is high. Skin, bone, and depot fat equilibrate much more slowly.

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DRUG DISTRIBUTION

Table-Blood Perfusion Rate


Organ Perfusion Rate (ml/min/ml of tissue) % of cardiac output

Bone 0.02 5
Brain 0.5 14
Fat 0.03 4
Heart 0.6 4
Kidneys 4.0 22
Liver 0.8 27
Muscle 0.025 15
Skin 0.024 6

It would be expected that total drug concentration would rise most rapidly in these organs.
Certain organs such as the adrenals (1.2/0.2%) and thyroid (2.4/1%) also have large perfusion
rates.

As an example; thiopental gets into the brain faster than


muscle, whereas, penicillin gets into muscle more quickly
than it gets into brain.

In brain, perfusion or membrane permeability limits


drug transport or distribution. Thiopental diffuses readily,
thus perfusion limits its distribution. Since perfusion is
higher to the brain than to muscle, transport to the brain is
faster. Penicillin less readily diffuses thus it is diffusion
which limits penicillin distribution. Muscle diffusion is
easier thus distribution into muscle is faster
for penicillinthan distribution into brain.

Lipid Solubility
Lipid solubility will affect the ability of the drug to bind to plasma proteins and to cross lipid
membrane barriers.
Very high lipid solubility can result in a drug initially partitioning preferentially into highly
vascular lipid-rich areas. Subsequently these drugs slowly redistribute into body fat where
they may remain for long periods of time.

Effects of pH
Effects of pH on the partitioning or "trapping" of drugs will not be as dramatic as those seen
between the stomach and plasma since the pH differences are not as great. Nevertheless, even
small pH differences have significant effects and so acidic drugs will still tend to accumulate
where the pH is higher while bases do the reverse.
The rate of movement of a drug out of circulation will depend on its degree of ionization and
therefore its pK.

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DRUG DISTRIBUTION

Changes in pH occurring in disease may also affect drug distribution. For example, blood
becomes more acidic if respiration is inadequate. Also, the pH of milk can increase as much
as 0.7 of a pH unit in animals with mastitis.

Capillary Permeability
The ability of a drug to reach various tissues will depend on the permeability of the
capillaries at the site in question. For example, the capillaries in liver are extremely
permeable, while those at the blood-brain barrier lie at the other extreme. Drugs can pass
through the epithelial cells or between them through the gap junctions.
Thus, molecular size is the major factor affecting the permeability of water-soluble drugs
across capillaries.

Pore Diameter (Å)


Intestinal epithelium 4
Capillary endothelium 40-80
Muscle capillaries 60
Glomerular capillaries 75-100
Glomerular endothelium 1000
Liver capillaries 1000

Passage of drug into the CNS


The largest pores are extremely permeable, allowing the passage of all but the largest of
proteins. In contrast, the pores in muscle allow only very small amounts of albumin to pass.
Drugs can pass into the CNS through the capillary circulation (through the blood-brain
barrier) or via the cerebrospinal fluid (through the choroid plexus). In both cases, the barriers
are similar to those encountered for the entry of a drug into the cytoplasm of a typical cell.
Thus, except when a drug has a specific uptake mechanism, only small, lipid-soluble drugs
are able to enter the CNS.

Inflammation of the epithelial layer may increase its permeability and allow charged and,
therefore, normally impermeant drugs (for example, penicillin and streptomycin) to attain
therapeutic concentrations in meningitis.

Passage of drug across the placenta


The placenta is not an effective parrier to most drugs. This is why the utmost care must be
taken when administering drugs to pregnant animals. Only highly ionized drugs and drugs
with low lipid solubility are excluded. Drugs such as oxytocin are vulnerable to placental
enzymes and so do not pose such a risk to the fetus.
Drug Dilution in Body Water

Body water constitutes as much as 75% of the total body weight of very lean animals and as
little as 45% in very fat ones. The average is about 60%. This is distributed between
intracellular fluid (~35% of body weight), interstitial fluid (~18%), blood plasma (~5%), and
transcellular fluid (~2%).

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DRUG DISTRIBUTION

Transcellular fluids are separated from the interstitial fluid by an epithelium. They include:

• Cerebrospinal fluid • Pleural fluids


• Aqueous humor of the eye • Peritoneal fluids
• Contents of renal tubules • Bile
• Urine in the bladder • Saliva
• Gland contents • Gastrointestinal secretions
• Synovial fluid in joints

The distribution of drugs between these body water compartments will depend on their
volume and the barriers (for example, lipid membranes, plasma binding proteins, pH
gradients) they encounter.

Accumulation at Other Sites


Cells: Many drugs accumulate in muscle and other cells. Since the pH difference between the
cytoplasm (~7.0) and the extracellular space (~7.4) is small, there is little pH trapping.
Accumulation is either due to active transport or, more commonly, to binding.

Fat: Highly lipid soluble drugs accumulate in fat (for example, chlorinated hydrocarbons).
Larger doses of lipid-soluble drugs may be necessary in obese animals.

Bone: Some drugs (for example, lead, fluoride, tetracyclines) are deposited in bone and teeth.

Drug Reservoirs
Sites other than the site of action can act as reservoirs for a drug. For example, plasma
proteins can sequester digitoxin and phenytoin, fat can sequester thiopental and
organochlorine pesticides, and bone can sequester tetracyclines and lead. The rate at which a
drug is released from a reservoir is governed by the same factors as those described for its
distribution. Such reservoirs can be useful in achieving a prolonged effect with an otherwise
short-acting drug.

Drug Residues in Food Animals


The existence of drug reservoirs and istes of prolonged sequestration is a major concern in
food animals. Residues can be found in muscle, milk, eggs, liver, etc. For this reason, many
drugs are not approved for use in food animals. For example, a drug will not be approved for
use in milking dairy cattle if drug residues can be detected for longer than 96 hours (8
milking) in milk.5

Plasma protein binding:


Most drug possess physicochemical affinity for plasma protein. Acidic drugs generally bind
to plasma albumin and basic drugs to a1 acid glycoprotein. Binding to albumin is
quantitatively more important. Extent of binding depends on the individual compounds .
No generalization for a pharmacological or chemical class can be made, for example:
Sulfamethazine 30%
Sulfadizine 50%
Sulfamethoxazole 60%
Sulfisoxazole 90%

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DRUG DISTRIBUTION

Increasing concentration of the drug can progressively saturate the binding site. Fractional
binding may be lower when large amounts of the drug are given . The generally expressed
percentage binding refers to usual therapeutic plasma concentration of the drug . The
clinically significant implications of plasma protein binding are:
1) Highly plasma protein bound drugs are largely restricted to the vascular
compartment and tend to have lower volumes of distribution

2) The bound fraction is not available for action. However it is in equilibrium with the
free drug in plasma and dissociates when the concentration of the latter is required
due to elimination. Plasma protein binding does provide temporary storage of the
drug.

3) High degree of protein binding generally makes the drug long acting, because
bound fraction is not available for metabolism or excretion, unless it is actively
extracted by liver or kidney tubules.

4) Generally expressed plasma concentration of the drug refers to bound as well as


free drug. Degree of protein binding should be taken into account while relating these
to concentration of the drug that are active in vitro e.g. MIC of an antimicrobial.

5) One drug can bind to many sites on the albumin molecule. Conversely more than
one drug can bind to same site. This can give rise to displacement interaction among
drugs bound to the same sites: drug bound with higher affinity will displace that
bound with lower affinity.

6) In hypoalbuminemia binding may be reduced and high concentration of free drug


may be attained, e.g. phenytoin and furosemide.*

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DRUG DISTRIBUTION

CLINICAL SIGNIFICANCE OF DISTRIBUTION


Distribution is one of the most significant pharmacokinetic terms. The delivery of a drug
from the plasma to the interstitiam results drug interaction at the site of action. If proper
distribution is occurred expected result is obtained. Imperfect distribution may either cause
toxicity or less pharmacological action.

Albumin and other plasma proteins are essentially contained within blood vessels, so bound
drug is similarly restricted. When more than 70-80% of the drug in plasma is protein bound,
it acts as a considerable reservoir for the drug. The effect of protein binding on the
distribution of a drug between blood plasma and transcellular fluid (relatively protein-free)
can cause toxicity. If the drug is highly protein bound, the volume of distribution will be very
low. On the other hand the drug of low affinity will in free form dominantly which creates a
chance of toxicity.

In brain tissue the blood brain barrier is a difficult way for drugs to cross. In the treatment
of epilapsy, lavodopa-the pro drug of dopamin is used because of the nice distribution
capacity of lavodopa.*

Two or more different drugs may bind to the same site on plasma proteins. Thus,
administration of a second drug may significantly affect the binding of the first drug.
Changes in binding have the greatest effect on the proportion of free drug when the percent
binding is high. Reducing binding from 98% to 96% will double the amount of free drug (2%
to 4%). With only 60% bound, the reduction would have to be 20% to double the free drug
(40% to 80%).
Groups on the protein molecules that are responsible for electrostatic interactions with
drugs include:
The of lysine and N- terminal amino acids,
The of histidine, the - S- of cysteine, and
The - COO- of aspartic and glutamic acid residues.
In order to achieve reasonably stable complexes, however, it is likely that in most cases the
initial electrostatic attraction is reinforced at close range by van der Waal's forces (dipole-
dipole; dipole-induced dipole; induced dipole-induced dipole) and hydrogen bonding.

EXAMPLE: At its therapeutic concentration, the anticoagulant, warfarin, is 97.4% bound. If


a therapeutic dose of the nonsteroidal anti-inflammatory drug, phenylbutazone, is
administered, bound warfarin decreases to 92%. Thus, free warfarin increases from 2.6% to
8% (3-fold). This increases the anticoagulant effect of warfarin considerably.6

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DRUG DISTRIBUTION

Conclusion

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Bibliography
1. http://www.merck.com/mmhe/sec02/ch011/ch011d.html
2. Britannica Ultimate Reference Suite-CD Edition2007
3. http://www.rxkinetics.com/pktutorial/1_3.html
4. http://en.wikipedia.org/wiki/Volume_of_distribution
5. http://web.vet.cornell.edu/public/pharmacokinetics
/freeDEF/other_factors.html#blood_flow
6. http://www.merck.com/mmhe/sec02/ch011/ch011d.html

* Essential of MEDICAL PHARMACOLOGY –KD Tripathi

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