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DRUG DISTRIBUTION
Distribution
Blood Brain Barrier
Protein Binding
DRUG DISTRIBUTION
• Drug distribution is a reversible transport of drug
through the body by the systemic circulation
• The drug molecules are carried by the blood to:
- target site/receptor
- non receptor tissues
- eliminating organs (liver, kidney)
- noneliminating tissues (brain, skin, muscle)
- placenta, milk
- bound to protein plasma and/or tissue
- deposit at bone, fat (slowly released)
Circulatory system
consists of a series of blood vessels:
• Arteries: carry blood to tissues
• Veins: return the blood back to the heart
Drugs molecules rapidly diffuse through a network
of fine capillaries to the tissue spaces filled with
interstitial fluid, further may diffuse from
interstitial fluid across the cell membrane into the
cell cytoplasm
The interstitial fluid + plasma water = extracellular
water
Drug distribution is generally rapid, and most small
drug molecules permeate capillary membranes
easily
The passage of drug molecules across
a cell membrane depend on:
• The physicochemical nature of both drug
( molecule size, lipid soluble/water soluble)
and the cell membrane (composed of
protein and bilayer phospholipid)
• Blood flow to organ/tissue (high or low
vascularization)
• Permeability of the membrane and the
capillary
• pH difference between plasma and tissue
Diffusion and Hydrostatic Pressure
The processes involved in capillary membrane transverses
• Passive diffusion : Fick’s law
dQ/dt = - DKA (Cp-Ct) / h
• The negative sign means net transfer of drug from inside the
capillary lumen into the tissue and extracellular sources
• Diffusion is spontaneous and temperature dependent
• Hydrostatic pressure = pressure gradient between the
arterial end of the capillaries entering the tissue and the
venous capillaries leaving the tissue and responsible for
penetration of water soluble drugs into spaces between
endothelial cells and possibly into lymph
• In the kidney high arterial pressure creates a filtration
pressure that allows small drug molecules to be filtered in
the glomerulus of the renal nephron
Distribution of drug entering the cell
with blood-flow induced mechanism
• Blood-flow induced drug distribution is rapid and efficient,
but requires pressure
• Blood pressure (BP) decreases when arteries branch into
small arterioles – flow speed lows – diffusion into
interstitial fluid depends on gradient concentration and
facilitated by the large surface area of the capillary network
• The average pressure of the blood capillary (18 mm Hg) is >
mean tissue pressure (-6mm Hg), net total pressure=24 mm
Hg higher in the capillary over the tissue
• This pressure is offset by osmotic pressure=24 mm Hg,
pulling the plasma fluid back into the capillary
• On average, pressure in tissue = pressure in capillary ≈ no
net flow of water
• At the arterial end, the blood enters the
capillary, the pressure at the capillary
slightly> than tissue – fluid leave the
capillary into the tissue – hydrostatic or
filtration pressure
• The filtrate water later returned to the
venous capillary due to lower venous
pressure than tissue called absorptive
pressure
• A small amount of fluid return to the
circulation through the lymphatic system
Distribution Space
• Intracellular space, 75% of BW:
- intracellular fluid
- solid cell compound
• Extracellular space, 22%
- plasma water 4% BW (intravascular fl)
- interstitial fluid 16-20% BW (easily difusable
interstitial fluid and poorly difusable fluid in skin, muscle,
cartilage, bone connective tissue)
- trancellular fluid, 1.5% BW (cerebrospinal, eye,
synovial, perilymph, endolymph, sinuses and small cavity
fluid)
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Distribution half-life, Blood flow, Drug
uptake by Organ
• Drug transfer from the capillary into the tissue fluid is
mainly diffusion process : h, D, (Cp-Ct) are important
factors in determining the rate of drug diffusion. If drug
distribution is limited by the slow diffusion, the process
is diffusion / permeability limited
• If drugs diffuse rapidly across the membrane that blood
flow is a rate limiting step in the distribution of drug,
the process is perfusion / flow limited.
Congestive heart failure - reduced filtration pressure
and blood flow
In disease condition:
• Drug with permeability limited : increased
distribution volume that cause inflammation and
increased capillary membrane permeability
• Renal/hepatic disease : osmotic pressure balance
may be altered due to albumin/ blood loss/changes
in electrolyte levels, resulting in net flow of
plasma water into the interstitial space (edema)
• This change in fluid distribution may partially
explain the increased extravascular drug
distribution during some disease states
• Drug Affinity for a tissue/organ =
partitioning and accumulation of the drug
in tissue
• The Distribution half-life or time for 50%
distribution= the time for drug distribution
• The factors that determine the distribution
constant of drug into an organ are related
to:
- blood flow
- volume of the organ
- partitioning of the drug into the organ
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kd = Q / V R
kd = first order distribution constant
Q = blood flow to the organ
V = volume of the organ
R = ratio of drug concentration in the organ tissue to drug
concentration in the blood (venous)
td1/2 = 0.693/ kd
R determined experimentally from tissue samples (the data
is only from animal tissue)
R ≈ Po/w
If each tissue has the same ability to store the drug, then kd
is only governed by Q and V. If Q is large, decreases the
distribution time, whereas if V is large, increases the
distribution time because a longer time is needed to fill a
Drug Accumulation
• The deposition or uptake of the drug into the tissue is
controlled by the diffusional barrier of the capillary
membrane and other cell membrane
• The brain is well perfused with blood, but many drugs
with good aqueous solubility which have high kidney,
liver and lung concentrations, yet little brain drug
concentration.
• The brain capillaries are surrounded by a layer of tightly
joined glial cells that act as a lipid barrier to impede the
diffusion of polar or highly ionized drugs.
• A diffusion limited model may be necessary to describe
the pharmacokinetics of these drugs that are not
adequately described by perfusion models
• The accumulation of drug into tissues is dependent
on:
- the blood flow
- the affinity of the drug for the tissue
• Drug uptake into a tissue is generally reversible
• The drug concentration in a tissue with low
capacity equilibrates rapidly with the plasma drug
concentration and then declines rapidly as the drug
is eliminated
• Drugs with high tissue affinity tend to accumulate
or concentrate in the tissue
• Drugs with a high lipid /water coefficient partition
are very fat soluble and tend to accumulate in lipid
or adipose tissue
Lipid soluble drugs and accumulation
• Partition from plasma (aqueous) into the fat tissue with reversible
process.
• Extraction of drug out of the tissue is very slow, remain 6-7 days
in adipose tissue, long after the drug is depleted from the blood
• Adipose tissue is poorly perfused with blood – drug accumulation
is slow
• Once the drug is concentrated in fat tissue, drug removal from fat
may also be slow
• To achieve the desired pharmacological effect, need a large initial
bolus of drug
• The distribution of lipophilic drugs will be different in thin versus
obese patients
• Some drugs are irreversibly bound to tissue protein with covalent
bound: purine and pyrimidine drugs used in cancer
chemotherapy are incorporated into nucleic acids, causing
destruction of the cell
• DDT: highly lipid soluble, remain years in fat
tissue
• Drug accumulate in tissue - binding to protein
tissue: Digoxin – highly binding to protein in
cardiac tissue – leading in a large volume of
distribution ( 440 L / 70 kg) and long t1/2 (40 hrs)
• Some drugs complex with melanin in the skin and
eye after long term administration of high doses of
phenothiazine to chronic schizophrenic patients
• Tetracycline – forms an insoluble chelate with
calcium on teeth and bones
• Amphetamin (phenilethylamine structure) ≈
norepinephrine, is actively transported into and
accumulated in adrenergic tissue (a specific uptake
system for catecholamin/ norepinephrine)
Permeability of Cell and Capillary Membranes
• Cell membrane vary in their permeability characteristics,
depending on the tissue
• Liver and kidney: more permeable to transmembrane
movement than capillaries in the brain. The sinusoidal
capillaries of the liver are very permeable and allow the
passage of large-molecular-weight molecules
• In the brain and spinal cord, the capillary endothelial cells
are surrounded by a layer of glial cells, which have tight
intercellular junctions, acts effectively to slow the rate of
drug diffusion into the brain by acting as a thicker lipid
barrier
• This lipid barrier, which slows the diffusion and penetration
of water-soluble and polar drugs into the brain and spinal
cord, is called the blood brain barrier
• The diameters of the capillaries are very small and the
capillary membranes are very thin. The high blood flow
within a capillary allows for intimate contact of the drug
molecules with the cell membrane, providing for rapid drug
diffusion
• For capillaries that perfuse the brain and spinal cord, the
layer of glial cells functions effectively to increase the
thickness of term h in Fick’s equation, there by slowing the
the diffusion and penetration of water soluble and polar
drugs into the brain and spinal cord
• In disease, the permeability of cell membranes, including
capillary cell membranes, may be altered by burns (on the
skin-large molecules can permeate inward or outward),
inflammation (meningitis) – drug uptake into the brain will
be enhanced
Apparent Volume of Distribution
• The concentration of drug in plasma or tissues
depends on the amount of drug systematically
absorbed and volume in which the drug is distributed
• Apparent volume of distribution, VD = the volume in
which the extent of drug distributed in the body,
represents the result of dynamic drug distribution
between the plasma and the tissues and accounts for the
mass balance of the drug in the body
• The volume of the system may be estimated if the
amount of drug added to the system and the drug
concentration after equilibrium in the system are known
• Volume of distribution, ( VD , L) = amount (mg) of drug
in body/drug concentration (C, mg/L) in plasma after
equilibrium
Apparent Volume of Distribution, Vapp
Vapp is different from VDss (compartment model)
Vapp = DB / CP
DB = VPCP + VtCt
DB = amount of drug in the body; VP = plasma fluid volume;
Vt = tissue volume; CP = plasma drug concentration; Ct =
tissue drug concentration
• For many protein bound drugs, the ratio DB/CP is not
constant every time, depends on the nature of dissociation
of the protein-drug complex and how the drug is distributed;
the ratio is best determined at steady state.
• Protein binding to tissue – apparent volume of distribution
increase. Some models: the drug distributes from the plasma
water into extracellular tissue fluid, where the drug binds to
extravascular proteins, resulting in a larger VD due to
extracellular protein binding
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• Drugs with polar compound (penicillin, cephalosporin, valproic
acid, furosemide) stay mostly within the plasma and
extracellular fluids – VD relatively low
• Drugs with lower distribution to the extracellular water are
more extensively distributed inside the tissues and tend to have
a large VD
• An excessively high VD (>body volume of 70 L) is due mostly to
special tissue storage, tissue protein binding, carrier, or efflux
system which removes drug from the plasma fluid : Digoxin, is
bound to myocardial membrane
• The high tissue binding is responsible for the large steady state
volume of distribution
• The greater drug affinity also results in longer distribution α
half-life in spite of the heart’s great vascular blood perfusion
• Imipramin is highly protein bound and concentrated in plasma,
yet its favorable tissue partition and binding accounts for a
large volume of distribution.
• TCA – large volume of distribution due to tissue (CNS)
penetrating and binding
Physicochemical Nature of group of drug
related to Drug Distribution
• Drug distributed only in plasma
• Drug distributed in plasma and extracellular fluid
• Drug distributed in plasma, extracellular fluid and
intracellular fluid
Drugs which have VD of 12 L : distributed in
extracellular fluid but not penetrated the cell
Drugs which have VD of 3 L (the plasma protein
binding are high, MW are high) : distributed only
in vascular compartment
Determinant of Drug Distribution
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Organ blood flow
Barriers to drug diffusion
Adipose tissue – drug accumulation
Tissue protein binding
Plasma protein binding
Drug transport
Ion trapping