Drug Distribution

Lailaturrahmi
0811012047

Distribution
In this process, drug molecules is transported
throughout the body by systemic circulation.
Drug molecules are carried by blood to the
receptor, which is responsible for drug action,
and nonreceptor, where adverse reaction
maybe occur .

Physicochemical nature of drug molecule and

its correlation with drug distribution
Solubility

of drug molecules

Cell membranes are composed of phospholipid

bilayer and protein, which act as lipid barrier for
drug uptake. So, lipofil drug molecules diffuses
more easily across the cell membrane than
hydrofil drug molecules

 Size

of drug molecules

Small dug molecules generally diffuse more

rapidly than large drug molecules.

Drug across the cell membrane by two

processes, passive diffusion and hydrostatic
pressure

Passive diffusion

Passive diffusion is the process by which drug

molecules move from an area of high
concentration to an area of low concentration

Passive diffusion is described by Ficks Law of

diffusion:
dQ

DAK (Cp

C t)

dt h
dQ/dt = rate of diffusion
D = diffusion constant
A = surface area of the membrane
K = lipid-water partition coefficient
h = thickness of the membrane
C p C t = the difference between the drug concentration in the
plasma (C p) and in the tissue (C t), respectively

Hydrostatic pressure

Hydrostatic pressure represents the pressure

gradient between the arterial end of the
capillaries entering the tissue and the venous
capillaries leaving the tissue.

Perfusion vs Diffusion

Perfusion occurs when a drug diffuses rapidly across

the membrane, and the blood flow becomes the rate
limiting step in the distribution of drug
Meanwhile, diffusion is the opposite. Diffusion
occurs when a drug diffuses slowly across the
membrane, and the permeability becomes the rate
limiting step in the distribution process

Factors in determining the rate of

distribution
Blood flow, tissue size, and tissue storage are
also important in determining the time it takes
the drug to become fully distributed
Drug affinity for a tissue or organ refers to the
partitioning and accumulation of the drug in
the tissue.

The time for drug distribution is generally

measured by the distribution half-life or the
time for 50% distribution
Distribution constant is determined by the
blood flow to the organ, the volume of the
organ, and the partitioning of the drug into the
organ tissue

kd = Q
VR
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)

We can obtain t by using this equation:

t = 0,693
kd

Blood flow is an important consideration in

determining how rapid and how much drug
reaches the receptor site.
If a tissue has a long distribution half-life, a
long time is needed for the drug to leave the
tissue when blood level decreases

The partition coefficient (P o/w) is defined as a ratio

of the drug concentration in the oil phase (usually
represented by octanol) divided by the drug
concentration in the aqueous phase measured at
equilibrium under specified temperature in vitro in an
oil/water two-layer system
A drug with large oil/water partition coefficient tends
to have high R values in vivo

Drug Accumulation

The accumulation of drug into tissues is dependent on

both the blood flow and the affinity of the drug for
the tissue
Drug uptake into a tissue is generally reversible
Drugs with high tissue affinity tend to accumulate or
concentrate in the tissue.
Irreversible binding of drug may occur when the drug
or a reactive intermediate metabolite becomes
covalently bound to a macromolecule within the cell,
such as to a tissue protein.

Permeability of Cell and Capillary

Membranes

Cell membranes vary in their permeability

characteristics, depending on the tissue
Under certain pathophysiologic conditions, the
permeability of cell membranes, including
capillary cell membranes, may be altered
The high blood flow within a capillary allows for
intimate contact of the drug molecules with the
cell membrane, providing for rapid drug
diffusion.

Apparent volume of distribution

The apparent volume of distribution, in

general relates the plasma drug concentration
to the amount of drug present in the body

Volume (L) =

Vapp = DB

amount of drug added to system (mg)

drug concentration in system after equilibrium (mg/L)

DB = VPCP + VtCt

CP
DB is the amount of drug in the body, VP is the plasma fluid
volume, Vt is the tissue volume, CP is the plasma drug
concentration, and Ct is the tissue drug concentration.

Drugs with lower distribution to the

extracellular water are more extensively
distributed inside the tissues and tend to have a
large VD.

Protein binding of Drugs

The formation of a drug protein complex is often

named drugprotein binding
Drugprotein binding may be a reversible or an
irreversible process.
Irreversible drugprotein binding is usually a result
of chemical activation of the drug, which then
attaches strongly to the protein or macromolecule by
covalent chemical bonding.
Reversible drugprotein binding implies that the drug
binds the protein with weaker chemical bonds, such
as hydrogen bonds or van der Waals forces.

Effect of Protein Binding on the Apparent Volume of

Distribution
The extent of drug protein binding in the plasma or tissue
affects V D. Drugs that are highly bound to plasma proteins
have a low fraction of free drug (f u = unbound or free drug
fraction) in the plasma water. The plasma protein-bound drug
does not diffuse easily and is therefore less extensively
distributed to tissues ().
Drugs with low plasma protein binding have larger f u,
generally diffuse more easily into tissues, and have a greater
volume of distributions.
Since the apparent volume of distribution is influenced by
lipid solubility in addition to protein binding, there are some
exceptions to this rule

Relationship of Plasma DrugProtein

Binding to Distribution and Elimination

In general, drugs that are highly bound to plasma

protein have reduced overall drug clearance. For a
drug that is metabolized mainly by the liver, binding
to plasma proteins prevents the drug from entering
the hepatocytes, resulting in reduced drug metabolism
by the liver. In addition, molecularly bound drugs
may not be available as substrates for liver enzymes,
thereby further reducing the rate of metabolism.

Determinants of Protein Binding

Drugprotein binding is influenced by a number of important
factors, including the following:
1. The drug

Physicochemical properties of the drug

Total concentration of the drug in the body

2. The protein

Quantity of protein available for drugprotein binding

Quality or physicochemical nature of the protein synthesized

3. The affinity between drug and protein

Includes the magnitude of the association constant

4. Drug interactions
Competition for the drug by other substances at a
protein-binding site
Alteration of the protein by a substance that modifies
the affinity of the drug for the protein; for example,
aspirin acetylates lysine residues of albumin

5. The pathophysiologic condition of the patient

For example, drugprotein binding may be reduced in

uremic patients and in patients with hepatic disease

Modeling Drug Distribution

Pharmacokinetic models can be used to predict these

pharmacokinetic changes due to changes in physiologic states
Perfusion and rapid equilibration within a region form the basis
for the well-stirred models that are used in many classical
compartment models as well as some physiologic
pharmacokinetic models.
The model also allows: (1) the mass of drug present in the
region can be monitored by multiplying the concentration with
its volume at a given time; and (2) the rate of drug elimination
from the site can be calculated by the product of clearance
times drug concentration.

Reference

Shargel, Leon, Susanna Wu-Pong, Andrew

B.C. Yu. 2004. Applied Biopharmaceutics and
Pharmacokinetics. New York: McGraw-Hill
Company