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Oral Delivery of Drugs
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SESSION ONE OF TIP PROJECT
TIP 2009 GEPHART
Advantages of taking oral drugs
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 Convenient (storage, portability, pre-
measured dose)
 economical
 non-invasive, often safer route
 requires no special training like IV drugs or
subcutaneous drugs require.
 Many are also available over-the- counter
TIP 2009 GEPHART
Disadvantages of taking oral drugs
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 Drug delivery is often erratic and incomplete
 It is highly dependent upon patient
compliance
 There are increased sources of drug-drug
and drug-nutrient toxins
 Many drugs degrade in GI environment
 Exposes drugs to first-pass effect
TIP 2009 GEPHART
Oral administration
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 The action of a drug is dependent upon it reaching its
site of action whereby it delivers an effective response
for therapeutic action.
 The important processes involved in the
pharmacokinetic phase of drug action are:
 Absorption of the drug
 Distribution of the drug
 Metabolism of the drug
 Elimination of the drug
TIP 2009 GEPHART
Absorption of the drug
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 Most orally administered drugs are absorbed
through the membranes of the GI tract.
 The rate of absorption will depend upon the
following:




the rate of dissolution of the solid (pill) into a solution
the pH of the medium containing the drug
the lipid-aqueous medium partition coefficient of the drug
the surface area of the absorbing region of the GI tract.
TIP 2009 GEPHART
Rate of dissolution of the solid into solution
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 When a drug is administered orally via tablet,
capsule, or suspension, the rate of absorption often is
controlled by how fast the drug particles dissolve in
the fluid at the site of administration. Hence, the
dissolution rate often is the rate-limiting (slowest)
step in the following sequence:
Solid Drug
dissolution
Step 1
TIP 2009 GEPHART
Absorption
Drug in
solution
Step 2
Drug in
Systemic
circulation
Rate of dissolution of the solid into solution
continued
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 Factors controlling dissolution, such as solubility, ionization, or
surface area, will then control the overall dissolution process.
 dC/dt = dissolution rate
 D is the coefficient of the dissolving material of the drug
 h is the thickness of the diffusion layer surrounding the dissolving
solid particles
 S is the surface area of the dissolution solid
 the drug concentration in the diffusion layer is equal to Cs
TIP 2009 GEPHART
pH of the medium containing the drug
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 Solubility is another factor determining the rate of
dissolution.
 Salts of weak acids and weak bases generally have much
higher aqueous solubility than the free acid or base;
therefore, if the drug can be given as a salt, the solubility
can be increased, and should have improved dissolution.
For weak acids:
For weak bases:
The dissolution rate of weak bases will decrease with increasing pH and the dissolution rate
of weak acids decreases with increasing hydrogen ion concentration.
TIP 2009 GEPHART
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The pH of a
particular drug has
an effect on the
movement of a drug
through a
membrane. It also
has an effect on the
dissolution of the
drug into the
solvent it is placed
in. Please go to the
link to the right to
complete this
activity.
TIP 2009 GEPHART
Please go to the following:
http://www.icp.org.nz/html/ph.htm
to complete the activity
Lipid-aqueous medium partition coefficient of the drug
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 A drug has to pass through a number of biological
membranes in order to reach its site of action.
 Organic medium/aqueous system partition
coefficients were the obvious parameters to use as a
measure of the ease of movement of the drug
through these membranes.
 The n-octanol- water system is frequently chosen
because it appears to be a good mimic of lipid
polarity and has an extensive database.
TIP 2009 GEPHART
Partition coefficient Definition
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The partition coefficient is the ratio of the
equilibrium concentrations of a dissolved
substance in a two-phase system containing
two largely immiscible solvents (water and
n-octanol) Since the differences are usually on a very large scale, Log
C water 
P
C oct .
TIP 2009 GEPHART
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(P) is used.
Partition coefficient (cont.)
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1-octanol
water
OH
O
H
H
More accurate results may be obtained if the organic phase is matched to
the area of biological activity being studied. n-octanol usually gives the
most consistent results for drugs absorbed in the GI tract while less polar
solvents give more consistent correlations for drugs crossing the bloodbrain barrier. More polar substances give more consistent values for
buccal absorption (soft tissues in the mouth).
TIP 2009 GEPHART
Surface Area
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 The surface area per gram (or per dose) of a solid
drug can be changed by altering the particle size
 Generally, as the surface area increases, the drug will
dissolve more rapidly. Therefore, many poorly
soluble and slowly dissolving drugs currently are
marketed in a micronized or microcrystalline form
TIP 2009 GEPHART
Drug absorption and permeation
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 Lipinski Rule of Five
 The Lipinski ‘rule of 5’ was derived by an analysis
of the key properties of 2,245 drug molecules
believed to have entered Phase II clinical trials.
 States that compounds are likely to have good
absorption and permeation in biological systems
and are more likely to be successful drug
candidates if they follow the rule of “five.”
TIP 2009 GEPHART
Lipinski Rule of Five
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




Five or fewer hydrogen-bond donors
Ten or fewer hydrogen-bond acceptors
 H-bond donors are expressed as the sum of OH’s and
NH’s and H-bond acceptors as the sum of O’s and N’s.
Molecular weight less than or equal to 500
Calculated logP less than or equal to 5
Compound classes that are substrates for biological
transporters are exceptions to the rule.
TIP 2009 GEPHART
Drug absorption
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 Drugs absorbed from the GI tract must pass through
the GI tract membrane, liver, and other organs in
order to reach the general circulation system.
 The physiology of drug absorption from the GI tract
has a direct effect on the bioavailability (F) of a drug.
TIP 2009 GEPHART
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The oral availability
of a drug can be
compared by
examining the drug
absorption and the
first pass metabolism
of the drug. The
activity provided here
will give you the
opportunity to
examine the
conditions under
which the drug will
reach the blood
stream. Please
complete all activities
provided.
TIP 2009 GEPHART
Please complete the activity at:
http://www.icp.org.nz/html/oral_availablity.html
Area under the curve
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 Since the area under the plasma concentration-time
curve (AUC) for a drug is a measure of the total
amount of drug reaching the general circulatory
system, the bioavailability of a drug may also be
defined in terms of the AUC as:
 F = AUC/dose
 Or absolute bioavailability is:
F = AUCpo/AUCiv
TIP 2009 GEPHART
Absorption and elimination
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 The increase in plasma concentration occurs as a drug is
absorbed. It is accompanied by elimination, which starts
from the instant the drug is absorbed.
 The rate of elimination increases as the concentration of
the drug in the plasma increases to the maximum
absorbed dose.
Figure 1: graph of the concentration vs. time
of a drug that is intravenously administered (red
arrow) and one that is orally administered (blue
arrow). (Lemke, Williams, Roche, & Zito, 2008)
TIP 2009 GEPHART
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The plasma
concentration (Cp)
is directly
proportional to the
dose rate, and
inversely
proportional to the
clearance. As you
complete this
activity, examine
the relationship
between the plasma
concentration, the
dose rate, and the
clearance.
TIP 2009 GEPHART
Please go to:
http://www.icp.org.nz/html/drug_clearance_1.html
to complete the above activity
Compartmental concepts
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 The most commonly employed approach to pharmacokinetic
characterization of a drug is to depict the body as a system of
compartments, even though these compartments often do not have
any apparent physiologic reality.
 The one-compartment model considers the body as a single
homogenous unit (central compartment). This simplest model is
particularly useful for pharmacokinetic analysis of plasma
concentration vs. time for drugs that are very rapidly distributed in
the body. The two-compartments model consists of a central
component, which includes the plasma and other highly perfused
organs, connected to a peripheral or tissue compartment. Each
compartment can be considered to include a group of tissues, fluids,
or parts of organs. (Lemke, Williams, Roche, & Zito, 2008)
TIP 2009 GEPHART
One and Two compartment models
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Figure 2: Schematic representation of the one-compartment (I) and
the two-compartment (II) models commonly used in
pharmacokinetics. Arrows represent transfer of a drug because of
the first-order process. C, central compartment (plasma, highly
perfused organs); P, peripheral (tissue) compartment. (Lemke,
Williams, Roche, & Zito, 2008)
TIP 2009 GEPHART
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The
compartment
models
illustrated show
the volume of
distribution of
drugs
dependent upon
their properties.
Please complete
all sections of
this activity.
Please click below to complete
above activity:
http://www.icp.org.nz/html/volume_of_distribution.html
TIP 2009 GEPHART
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The amount of time
it takes the
concentration of a
drug to fall to half
its original value is
known as its
biological half-life
(t1/2).
For drugs that
exhibit first order
elimination kinetics
t1/2 = 0.693/kel
TIP 2009 GEPHART
Half-life
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The half-life of a
drug is the time
it takes for the
concentration to
halve. Examine
the activity here
and look at the
relationship
between the
concentration,
volume
delivered and
the t-1/2 value.
TIP 2009 GEPHART
Please click below to complete
above activity:
http://www.icp.org.nz/html/half_life.html
(
Volume of distribution relationships to dosing
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Lemke, Williams, Roche, & Zito, 2008)
TIP 2009 GEPHART
Therapeutic effects and dosing of oral medications
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 When a single dose of a drug is administered orally, its
plasma concentration increases to a maximum value
(Cmax) at tmax before falling with time.’
 The change in plasma concentration-time curve for a
single oral dose shows the time (tlag) for the drug to reach
its therapeutic window concentration, the tmax, and the
Cmax.
 All of these measurements are useful in determining the
correct dosage form for a drug and also the selection of
analogues for development.
TIP 2009 GEPHART
Oral Dosing
Click here for video
Minimum toxic
concentration
Minimum effective
concentration
TIP 2009 GEPHART
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Dosing: Single dose
oral drugs can be
compared to multiple
dosing. Loading
helps to bring the
initial concentrations
up to an effective
concentration more
quickly. Compare the
different types of
dosing within the
activity provided.
Compare the
therapeutic windows
of each trial.
TIP 2009 GEPHART
Please click below to complete above
activity:
http://www.icp.org.nz/html/dose.html
Conclusion
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 The therapeutic effect of oral drugs depends upon the
absorption, distribution, metabolism, and elimination of the
drug within the body system.
 The absorption and distribution of a drug can be influenced
by the particle size, pH, partition coefficient, and the
molecular weight of the drug.
 The rate of absorption and elimination affect the therapeutic
levels that can be achieved within the body.
 Dosing of a drug is dependent upon the rate of absorption and
the rate of elimination. The kinetics of these processes help to
determine the frequency and dosage form of the drug.
TIP 2009 GEPHART
References
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 Lemke, T. L., Williams, D. A., Roche, V. F., & Zito, S. W.
(2008). Foye's Principles of Medicinal Chemistry .
Philadelphia: Wolters Kluwer.
 Lipinski's Rule of Five. (1997). Retrieved February 12,
2009, from Group Seminar Lipinski Rule of Five:
bioinfo3d.cs.tau.ac.il/Education/CS01a/GroupSeminar/Lip
inskiRuleOfFive.ppt
 Thomas, G. (2003). Fundamentals of Medicinal Chemistry.
West Sussex, England: Wiley.
TIP 2009 GEPHART