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Pharmaceutics II – Okamoto: 1/13/2005 1

Oral Drug Absorption

Factors Affecting Drug Absorption

 Small Intestine – Is the major absorptive organ.


o There is not much drug absorption in the colon (mostly water) or in the
stomach.
o There is about 27 feet of small intestine, so there is lots of time for
absorption.
o Drug absorption is affected by pH, solubility, and the stability of dosage
forms.
 Bioavailability – the amount of drug available for therapeutic purposes  how
much drug is available circulating throughout the body (in plasma as a free drug).
 Rate Limiting Factors to Drug Absorption  Bioavailability (Often measured
in the Plasma).
o Sources of Incomplete Drug Absorption – Limiting Factors (4)
 The Drug is not delivered from its formulation over an appropriate
time frame in solution form to those sites in the GI tract where it is
well absorbed (such as the small intestine).
• You want the drug into solution form by the end of the
small intestine.
 Decomposition of the drug in the GI tract or complexation into a
non-absorbable form.
• Decomposition – may be hydrolysis reactions (remember
from pharmaceutics I).
• Complexation – How smaller molecules interact with
larger molecules
o Such as drug interactions with proteins, or ligands
and receptors  these are regulated by non-
covalent interactions.
o Example: Drug molecules bind to albumin, so it is
limited because it does not bind to the target, such
as another receptor.
o Ex: Very hydrophobic drugs partition into oil
droplets  these oil droplets come from the fat in
our diet, drugs will partition into fat globules and
then will not be available to bind to its target (why
“take on an empty stomach” is important).
 Inefficient Transport across the gut wall (the apical to basolateral
direction).
• This is often seen with ionic, ionized or hydrophilic
molecules.
• The drug can’t be transported if the transport system is
saturated (all the appropriate receptors are filled with drug
molecules).
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Oral Drug Absorption

Efflux Pump – Lumen Hydrophilic Drug


pumps drug out of the cell
Drug
There is a physiological
back into the lumen (efflux pump) and
physical barrier (cells)

Drug

Blood

Drug Metabolism or Elimination en route to systemic circulation.



• The liver plays a large role in drug metabolism; drugs are
absorbed in the small intestine, and they enter portal
circulation and go to the liver where they may be
metabolized.
• Intestinal epithelial cells play a significant role in
metabolizing drugs.
 GI Tract as a Dynamic System – Affects Drug Absorption
o Transit time of the dosage form/drug
o Appropriate time frame of release and absorption must be greater than
decomposition and complexation.
 Has to do with the formulation of the tablet (for example)
• Disintegrant – particles of the drug (or crystals) try to get
individual drug molecules to go into solution  it is the
individual drug molecules that are being absorbed.
o Need Disintegration and Dissolution to occur in the
GI tract so the individual drug molecules can be
absorbed.

Drug in systemic circulation

Gut/Liver metabolism
Biliary Excretion

Decomposition Drug in solution at uptake sites


Complexation
Absorption

Release Transit (depends on GI


motility)

Decomposition
Complexation
Absorption Drug in solution at uptake sites

Gut/Liver metabolism
Biliary Excretion
Figure I. Steps in drug
Drug absorption and sources of incomplete bioavailability
in systemic circulation
following oral administration of a solid dosage form.
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Oral Drug Absorption

Biopharmaceutics Classification Scheme (BCS): - This scheme is used to


Categorize all drugs taken orally
 There are four classes: I – IV, this is based on Solubility and Permeability.

Table I. The Biopharmaceutics Classification Scheme

Class I Class II
HIGH SOLUBILITY LOW SOLUBILITY
HIGH PERMEABILITY HIGH PERMEABILITY

Class III Class IV


HIGH SOLUBILITY LOW SOLUBILITY
LOW PERMEABILITY LOW PERMEABILITY

 Dissolution Testing – Determine which class the drug belongs to.


o Class I – High absorption is predicted, but testing still needs to be done
for rapid release.
 FDA approves that if you can show that a drug fits in class I, it
does not have to undergo absorption testing (which is laborious).
• These drugs include “me too” drugs  derivatives of
parent drugs that have already undergone testing.
• Toxicity testing still needs to be done.
• Testing still needs to be done to verify the drug will be
released in a timely matter, ex. Griseofulvin fashion.
o Class II – Limited by solubility, but has high permeability (how well a
molecule moves across a barrier), so the dissolution of the drug is rate
The optimal limiting (two types).
situation for class
II Drugs would  Equilibrium – lack of fluid volume for dissolution  there is not
be to have a low enough liquid in the gut for the drug to go to equilibrium.
dose / • The GI tract has about 5-10L entering the lumen in a 24
permeability hour period.
ratio.
• Ex. Griseofulvin (not very soluble, but permeable). The
solubility is 15mcg/mL, the therapeutic dose is 500mg, and
the volume of fluid needed is 33L.
o The Key to delivering the therapeutic dose  the
GI is a dynamic (not closed) system, so the dose can
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Oral Drug Absorption
be delivered. The drug is absorbed out of the lumen
into the blood stream, so the absorption is
enhanced…

Lumen There is an instant dilution effect; so there


is a positive driving force.
Griseofulvin ≤ 3mcg/mL will not see any negative
= 15mcg/mL effects

If the derivatives of grisiofulvin (for


example) are not so permeable, then more
molecules in the lumen that are not being
transported…this should increase
permeability because building up the
concentration  so will see more with
drugs that are absorbed through
membrane transporters.

Blood

 Kinetic – the drug dissolves too slowly for the entire does to
become dissolved before the drug has passed the absorption site
(ex. Digoxin)
• The rate of solution (not the solubility) is the issue!
• Once the Drug is in the blood, it will be carried away; so
for every molecule that goes into the blood stream, another
will go into solution.
• Once the drug is in the blood:
o It could be metabolized by the liver.
o Could bind to albumin (so it is no longer free in
solution).
o Can bind to its target; then it is pulled out of the
blood stream.
*The process of achieving the therapeutic dose of a drug is trial and error*
 Class III – Need to have rapid dissolution to increase contact time.
o The drugs are highly soluble, but not very permeable
o Ex: Ionized drugs or hydrophilic drugs  you want to increase the
dissolution time to increase the contact time so more of the drug can be
absorbed.
 But the longer the drug is in solution, there is an increased chance
of degradation.
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Oral Drug Absorption

The Saturated or Unstirred Layer – the


drug in this layer is dissolved to the
maximum.

The Rate of Dissolution slows as the concentration in the bulk solution approaches the
saturated concentration  you end up with zero…which means everything is at
equilibrium, so the solution is saturated.

Drug Particles in the Solution


1. They are only absorbed from the surface because only part is exposed to water.
2. The thickness of the unstirred layer depends on how well the solution is being
stirred.
3. The Rate of Dissolution depends of the saturating content of the drug molecule
and the thickness of the unstirred layer.
a. The concentration affects the amount of material getting into solution over
time; how long does it take for drug molecules to go from the unstirred to
the bulk solution.

 Class IV – these are compounds that are poorly absorbed, there is a negative
effect of poor formulation.
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Oral Drug Absorption

Physiochemical and Physiological Parameters Important to Drug


Dissolution in the GI.

Table 2. Physiochemical and Physiological Parameters Important to Drug Dissolution in


the GI Tract.

Factor Physiochemical Physiological


Parameter Parameter Very
Surface Area of the Drug Particle size, wettability Surfactants in gastric juice Important
and bile Table
Diffusivity of the drug Molecular size Viscosity of luminal
contents
Boundary layer thickness Motility patterns and flow
rate
Solubility Hydrophilicity, crystal pH, buffer capacity, bile,
structure, solubilization food components
Amount of Drug already Permeability
dissolve
Volume of solvent available Secretions, co administered
fluids.

Xd = amount of drug in
Solution
 The Kinetics of drug dissolution: A = effect of surface area of
the solid drug (smaller
dXd = A * D (Cs - Xd/V) particles have a larger
surface area)
dt δ D = Diffusion coefficient
δ = effective diffusion
C = Xd / V Boundary layer thickness
adj. To dissolving
surface  the thickness
 The Effect of Permeability: “Sink” conditions. of the unstirred layer.
o Body Fluid Volumes Cs = saturation solubility  the
 Total – 40L most amount of drug that can
dissolve in the solution.
 Extracellular – 15L V = the volume of the dissolution
 Intracellular – 25L medium.
*How much drug is left in the “sink” (lumen)*
o Highly permeable drugs  sink conditions maintained
with respect to time < 20% of the drug left in the
lumen.
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Oral Drug Absorption
o Less permeable drugs  there is a buildup of drug
In the lumen, therefore the dissolution rate decreases
With respect to time  this negatively affects bioavailability.

“SINK” CONDITIONS

10L the [ ] = .4 molecules / L

40L the [ ] = .1 molecules / L

The drug molecules go from the G.I tract  body; there is an instant dilution
effect; so there is ALWAYS a [ ] gradient when you compare a molecule in the
body versus the G.I tract.
 Biological processes make an even larger gradient into the bloodstream…this
is seen in highly permeable drugs.

Biological Parameters

 Genetic Variability
o Intersubject – There are genetic differences found between two different
individuals.
 These genetic differences are typically found in genes that code for
proteins  they are common and are called polymorphisms.
• Polymorphisms affect the function of the protein some 
this explains why there are ethnic differences in the
capacity for people from different ethnic groups to
metabolize drugs.
o For example, Asians vs. Caucasians  Cytochrome
p450 may be less active in the Asian population, so
the bioavailability of the drug will be greater.
o Other genetic variables that affect drug delivery is
carrier transporters.
 Polymorphisms can affect how efficiently
transporters can carry the drug across
epithelial cells.
o G.I motility may also be different from person to
person.
o Intrasubject – There are differences within you.
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Oral Drug Absorption
G.I tract conditions can change minute to minute, or within the
day (circadian rhythm).
• Ex: when you sleep, there is not any food, so GI motility
slows
 There are changes from Fed vs. fasted states
• Acid secretion
• Enzyme secretion
• G.I motility
• Bile Salts/acids – the concentration is higher during a meal
that during a fasted state.
 Stress can cause changes:
• Can lead to hyper gastric acid secretion
• Motility.
 Luminal Composition
o pH
 How does pH affect oral drug delivery?
• Degradation: Hydrolysis, such as acid catalyzed
hydrolysis
• Ionization/protonation – this affects the solubility – it
could increase or decrease the solubility
o At a low pH: basic drugs will be more soluble
because protonated weak acids exhibit poor
solubility.
o But if you increase solubility, you also increase the
chance of degradation; so if the drug is not soluble
in low pH, it is protected in the stomach  this
helps protect against hydrolysis.
 Gastric  fasted (pH is 1.4 – 2.1) vs. fed state (pH 3 – 7).
• The pH in the fasted state is low relative to the fed state.
• A person typically returns to the fasted state from the fed
state in about 2-3 hours.
• During a fasted state:
o There are not very many components in the
stomach, so the acid that is secreted dominates and
the fluid is acidic.
• During a Fed State:
o Much more acid is pumped out, but the food
becomes degraded and may serve as a buffer  so
the buffer capacity in the fed state is higher, and so
is the pH.
 Hypo/achlorhydria  over the age of 65 (10 – 20%, blocker
therapy.
• People > 65 years old have lower acid secretion naturally.
• People on PPI’s don’t have any acid secretion.
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Oral Drug Absorption
o A higher than normal pH affects the bioavailability
of drugs.
 Intestinal
 Colonic  bacterial activity can lower the pH of the colon to about
5 because of undigested carbohydrates that are being converted to
short fatty acid chains.
• Bacteria metabolize carb’s and then excrete protons as a
byproduct which creates an acidic environment.

Table 2. pH in the Small Intestine in Healthy Humans in the Fasted and Fed States.

Location Fasted State pH Fed State pH


Mid – Distal Duodenum 4.9 5.2
More Basic 6.1 5.4
6.3 5.1
There are only
6.4 minor changes in
the fed vs. Fasted
Jejunum More Basic 4.4 – 6.5 state  this is
5.2 – 6.0
6.6 relatively constant 6.2
environment in
Ileum 6.5 issues related to
6.8 – 7.8
6.8 – 8.0 solubility and 6.8 – 8.0
hydrolysis.
7.4 7.5

 Buffer capacity – The capacity of a volume of liquid to resist changes in pH 


the pKa of a molecule must be within certain parameters of the pH to be buffered.
o Broken down food provides buffering capacity.
o This is very important, because it helps to predict the affects in the
solubility and degradation of drug molecules.
 Surfactants – this is the effect of bile salts and bile acids  they function to help
emulsify the oily components in your diet…also helps emulsify the hydrophobic
drugs.
o Two things happen with surfactants:
 They help wet the solution/particle  wetting
• Then the water treats the particle as a hydrophilic entity;
this reduces the surface tension of the water, so it helps the
water and the particle to interact…
 Facilitates the solubilization into micelles
• Facilitates the hydrophobic drug to get out of fatty
environment, and stays into the aqueous solution.
(Remember from Pharm I  decrease interfacial tension?).
• Helps drug molecules diffuse through the solution to
Enterocyte, where it can then be absorbed.
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Oral Drug Absorption
 Enzymes – in particular pancreatic enzymes  which aid in the digestion of
dietary products.
o Proteolytic enzymes have a minute affect of drug absorption, unless the
drug is a protein  the protein is broken down into amino acids, and it
then can act as a buffer.
o Enzymes may affect complexation.
 Drugs may be bound to proteins, enzymes degrade the protein, and
then the drug is released and free to be absorbed.
o Drugs may be degraded by proteo enzymes if the drug looks like a protein
 Ex. Insulin; you cannot pop an insulin pill  it must be injected
because the insulin will be degraded in the G.I tract.
o Enzymes also degrade fat  Lipases hydrolyze fat (very important!!)
 If fats are rapidly hydrolyzed and absorbed, the absorption of very
hydrophobic drugs may be affected.
 Look at griseofulvin table to see how dietary fat affects the
absorption of hydrophobic molecules.

Figure 7. This is a comparison of the effects of different types of food intake on the
serum griseofulvin levels following the 1.0g oral dose  griseofulvin concentrations
under different conditions.

High Fat

How much of
the drug
Concentration

Oleomargine 60g shows up in


the blood
stream.
Oleomargine 30g

No Fat – such as Adkins diet


Fasting

Time

 Volume – there is only a certain volume of liquid in the G.I tract.


o So there are equilibrium limited drugs
o The amount of G.I fluids depend on fed (more volume) vs. fasted state.
o Fluid is secreted into the lumen of the G.I tract (it is later recovered). See
graph on handout.
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Oral Drug Absorption

Hydrodynamics in the GI Tract –


o Mixing patterns: different types of motility that can change minute to
minute.
 Peristalsis – moving food along the G.I tract  this type of
movement effects the transit time.
 No activity (quiescence)
 Segmental Movements  2cm…the contents of the G.I tract are
squished; this facilitates absorption and dissolution.
 Propagative movements (short or long range)  15cm for short
 Tonic contractions
o Flow Rates – Transit time; how long particles stay in the G.I tract.
 Small particles and water have fast transit time, while fats have a
physical chemical issue  when you stand up, the fats float to the
top of the surface of the stomach.
 Caloric density affects the transit time.
o Small Intestine residence time-little difference
 There is not much difference in the fed vs. fasted state: It takes
several hours under normal circumstances  the transit time is
regular and constant.
o Residence time in colon
 It takes 24 hours to 3 days  there is a lot of mixing that occurs in
the colon; it is not an absorptive organ.
o SIF – Stimulated Intestinal Fluid
 Class I or II can do dissolution testing  mix salts and enzymes
and buffers to approximate as closely as possible the contents in
the lumen of the stomach.