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Drug
Blood
Gut/Liver metabolism
Biliary Excretion
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.
Pharmaceutics II – Okamoto: 1/13/2005 3
Oral Drug Absorption
Class I Class II
HIGH SOLUBILITY LOW SOLUBILITY
HIGH PERMEABILITY HIGH PERMEABILITY
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.
Pharmaceutics II – Okamoto: 1/13/2005 5
Oral Drug Absorption
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.
Class IV – these are compounds that are poorly absorbed, there is a negative
effect of poor formulation.
Pharmaceutics II – Okamoto: 1/13/2005 6
Oral Drug Absorption
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.
Pharmaceutics II – Okamoto: 1/13/2005 7
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
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.
Pharmaceutics II – Okamoto: 1/13/2005 8
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.
Pharmaceutics II – Okamoto: 1/13/2005 9
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.
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
Time