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Last edited: 7/26/2022
PHARMACOKINETICS | DRUG ABSORPTION
Pharmacokinetics | Drug Absorption
Medical Editor: Sarah Abimhmed
OUTLINE
I) ROUTE OF ADMINISTRATION
III) FACTORS AFFECTING
II) MECHANISM OF ABSORPTION ABSORPTION
(A) TRANSPORT MECHANISMS
(A) PH
(B) ABSORPTION IN OTHER ROUTES
(B) BLOOD FLOW
(C) TOTAL SURFACE AREA +
CONTACT TIME
(D) P-GLYCOPROTEIN
IV) BIOAVAILABILITY (F)
V) FACTORS AFFECTING
BIOAVAILABILITY
(A) SOLUBILITY OF THE DRUG
(B) INSTABILITY OF THE
VI) REVIEW QUESTIONS
VII) REFERENCES
ENVIRONMENT
(C) FIRST-PASS EFFECT
I) ROUTE OF ADMINISTRATION
Absorption is the administration of a drug and the process of getting it into the circulation, therefore, understanding different
routes of administration is important.
o Enteral routes:
 p.o. (per os): oral or enteral route
 p.r. (per rectal): rectal route
 Buccal: between the lip and the teeth
 Sublingual: under the tongue
o Parenteral routes (via injection):
 ID (Intradermal injection): in the dermis layer
 SC or SubQ (Subcutaneous injection): into the
subcutaneous tissue
 IM (Intramuscular injection): into the muscle
 IV (Intravenous injection): into a vein
 Inhalation agent: into the lungs
o Local routes:
 Topical route: on the skin
The most common routes of administration are:
o p.o. (oral) → in outpatient
o IV (intravenous) → in the hospital
Figure 1: Routes of Administration
Figure 2 Dosage forms
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II) MECHANISM OF ABSORPTION
The mechanism of absorption of the drugs is best explained with the oral route of drug intake:
Figure 3: The route the drug takes when
administered orally
TRANSPORT MECHANISMS
The transport mechanisms by which different drugs pass through the cell membrane depend on the characteristics of the drug,
such as size, solubility, and charge.
(1) Simple (Passive) Diffusion
(3) Active Transport
Drug characteristics: Small or Hydrophobic (lipophilic)
Mechanism: Passive movement of molecules from areas
of high concentration to areas of lower concentration
Drug characteristics: Large or Hydrophilic
Mechanism: Movement of molecules from areas of lower
concentration to areas of higher concentration (against its
concentration gradient), and this requires energy (ATP).
Figure 4: Passive Diffusion
(2) Facilitated Diffusion
Drug characteristics: Large or Hydrophilic
Mechanism: Passive movement of molecules from areas
of high concentration to areas of lower concentration via
specific transmembrane proteins
(4) Endocytosis (Bulk Transport)
Drug characteristics: Very large (e.g., Vitamin B-12)
Mechanism: movement of macromolecules through the
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cell membrane. The drug binds onto receptors on the cell
membrane, this triggers invagination of the drug in a
process called ‘Endocytosis’. Then this drug is pushed
out of the cell (to the vasculature) by ‘exocytosis’.
Figure 5: Facilitated Diffusion
Figure 7: Endocytosis
Mechanism
Drug Characteristics
Passive Diffusion
High → Low
Hydrophobic. Small
Facilitated Diffusion
High → Low
Needs protein carrier
Hydrophilic
Large
Active Transport
Low → High
Needs ATP to be transported
Hydrophilic
Large
Endocytosis
Needs receptor-mediated endocytosis, then exocytosis to
the vasculature
Too Large
(e.g., Vit. B12)
Table 1: Summary of Transport Mechanisms
Rectal route: the drug has to move across the gastrointestinal tract layers in there
Intradermal, Subcutaneous, Intramuscular: the drug has to pass through different layers of the skin and tissues before it gets to
the nearby capillaries
Intravenous: the drug moves directly into the bloodstream (without having to pass through a membrane)
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PHARMACOLOGY: NOTE #1.
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III) FACTORS AFFECTING ABSORPTION
(A) PH
●Drugs usually exists in 2 forms, a weak acid, HA (e.g. Aspirin) and a weak base, BH+ (e.g. amphetamines).
(1) Weak Acids
(2) Weak Bases
HA dissociate into H+ and A●If there is a weak acid, A- is more difficult to be absorbed
because it is charged (polar), the phosphate groups of the
cell membrane are negatively charged so they will repel
the charged molecule.
BH+ dissociates into B + H+
●Therefore, in order for the weak acid drug to be absorbed,
it needs to exist in the HA form as it is not charged (nonpolar). The reaction needs to go in the opposite direction.
Figure 8: Dissociation equation of weak acids
●For the reaction to go in the opposite direction, there needs
to be more protons inside the environment of the drug.
●BH+ is polar, not easily absorbed.
o B is non polar, easily absorbed.
▪ The reaction needs to shift to make ↑ B (to the
right in the figure below)
●A way in which this can be achieved is by ↓ the protons
in the environment so that the reaction can shift to make
more protons (to reach equilibrium).
●To ↓ the protons, the environment needs to be more
alkaline.
o The reaction shifts to make ↑ B molecules that are in a
non-polar, non-charged form which are more easily
absorbed.
●The area in which weak base drugs are best absorbed in
is the distal ileum.
(i) Le Chatelier’s Principle:
●For example, if the drug is an acidic environment, the
number of protons will increase and according to le
chatelier’s principle when there is an increase in
concentration on one side, the reaction will shift to
establish equilibrium (to the left according to the equation
in the figure above).
●The concentration of the non-polar weak acid will ↑.
o Therefore, in an acidic environment, a weak acid will
be in the HA form, this is will be easily absorbed
across the phospholipid bilayer and into the blood
stream.
Figure 10: Absorption of weak basic drugs is enhanced in
alkaline environments
Figure 9: Absorption of weak acid drugs is enhanced in acidic
environments
●This is important because when giving a weak acid drug, it
needs to be in an acidic environment in order to enhance
the absorption of the drug.
o The most acidic area that weak acid are best
absorbed in is the proximal duodenum.
(B) BLOOD FLOW
●Adequate blood flow is needed to supply particular organs.
o Absorption is the movement of the blood into the
bloodstream, if there is ↓ blood flow to a particular
organ which requires a specific drug to be absorbed,
there will be ↓ absorption.
There are certain situations in which there is ↓in blood flow:
●Shock state (e.g. septic, hypovolemic, neurogenic)
o There is ↓ blood flow to the organs that absorb the
drug (GI, Skin, etc.) Therefore, lower amounts of the
drug will be absorbed into the bloodstream, as there is
not enough perfusion to the GIT and Skin.
o This occurs if the drug is taken orally, rectally or
via the skin.
●The only way to ensure that the blood gets into the blood
is via IV administration.
o This is why patients in these state receive drugs via
the IV route.
Pharmacokinetics | Drug Absorption
Figure 11: Decreased blood flow decreases perfusion to
particular organs which then decreases absorption.
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(C) TOTAL SURFACE AREA + CONTACT TIME
(1) Contact Time
●If the patient has ↑ motility in the GI tract (e.g. diarrhea),
the drug will pass by so fast that there will not be enough
contact time for absorption to occur and enter the blood
stream.
o Therefore in case of diarrhea, absorption of the drug ↓
as there is ↓ contact with the cells of the GIT.
(2) Total Surface Area
●The intestines have a large surface area, this is mainly
due to the villi and microvilli.
●In case of diseases that destroy the villi and microvilli,
surface area of the intestines ↓.
o This occurs in IBD, celiac, gastroenteritis, etc.
●The absorption of the drug will consequently ↓.
●On the other hand, if the patient has slow transit time, as
in the case of constipation, there is so much time for the
drug to be absorbed (↑ contact time with the cells of the
GIT)
o Therefore there is ↑ absorption.
Figure 13: Decreasing Total Surface Area (as in the case of
diseases such as IBD, celiac, etc.) decreases absorption
Figure 12: Contact time and absorption are directly proportional
(D) P-GLYCOPROTEIN
●When a drug is ingested orally, it passes through the cell
membrane via different mechanisms.
REMEMBER:
Mechanisms of drug transportation:
• Passive Diffusion
• Active Diffusion
• Facilitated Diffusion
• Endocytosis
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●There are special transporters in the GIT can affect
absorption, this is the case with P-Glycoproteins.
o P-Glycoprotein are found in the apical surface of the
cell.
o They inhibit the process of drug absorption by pushing
the drug back into the GIT instead of letting it pass to
the blood stream.
▪ This leads to multi-drug resistance (MDR).
Figure 14: P-Glycoproteins found in some cases inhibits
absorption and leads to multi-drug resistance
Table 2: Summary of factors affecting absorption
Factors Affecting
Absorption
↓ Absorption
↑ Absorption
Weak acid drugs in alkaline environments
Or weak base drugs in acidic environments.
Weak acid drugs in acidic environments
Or weak base drugs in alkaline
environments.
↓ perfusion to organs that absorb drugs (e.g.,
skin, GIT) this can occur in shock states.
↑ perfusion to organs that absorb drugs
↓ contact time (e.g., diarrhea)
↑ contact time (e.g., constipation)
Total Surface Area
↓ Total Surface Area, this occurs in diseases
that destroy the brush border of the GIT cells.
↑ Total Surface Area
P-Glycoprotein
If P-Glycoproteins are found in apical surface
of GIT cells.
No P-Glycoproteins
pH
Blood Flow
Contact Time
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Pharmacokinetics | Drug Absorption
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IV) BIOAVAILABILITY (F)
●This is one of the most important components of absorption.
(i) Definition:
●This is the fraction of the drug that enters the systemic circulation.
(2) Bioavailability with IV vs Oral Administration
●When a drug is administered via the IV route, it does not pass through any membrane.
o The amount of drug that is administered and that gets absorbed in the bloodstream is 100%, therefore bioavailability of IV
drugs is 100%.
●However, if a drug is administered orally or through other routes that require passing through membranes, absorption is
affected by various factors such as pH, blood flow patterns, surface area, contact time, solubility of the drug, size of the drug,
etc.
o All the blood that is administered will not enter the blood stream so bioavailability will not be 100%.
(i) Calculating Bioavailability (F):
(ii) Bioavailability is determined via this formula:
●If the drug is given IV, it will reach 100% and with time it
will decrease until it is completely eliminated as it will be
metabolized and excreted.
o The area under the curve (AUC) will determine that.
●So, if 100 mg of the drug is given and only 50 mg is
absorbed, therefore the bioavailability is 50%.
Figure 15: Graph showing bioavailability of IV administered
drugs (blue) and orally administered drug (brown)
●If the drug is given orally, the concentration will rise but it
would not reach 100%. With time the concentration will fall
as it becomes metabolized and excreted.
Figure 16: Bioavailability with IV vs Oral Administration, orally
administered drugs have lower bioavailability than IV
administered drugs.
V) FACTORS AFFECTING BIOAVAILABILITY
(A) SOLUBILITY OF THE DRUG
Hydrophobic (lipophilic), small, and nonpolar drugs
can easily pass across the cell membranes (of the GIT)
and get into the bloodstream and so they have
(↑) Absorption and (↑) Bioavailability (F)
Hydrophilic and large drugs cannot easily pass and so
they have (↓) Absorption and (↓) Bioavailability (F)
(B) INSTABILITY OF THE ENVIRONMENT
(1) Stomach and Intestinal Metabolism
On oral administration of the drug, e.g., penicillin G, as it
reaches the stomach, it gets destroyed (metabolized) by
protons [H+] from the HCl (hydrochloric acid) which are
released by parietal cells, and this leaves almost none of
the drug to be absorbed into
the bloodstream, and
ultimately this leads to (↓)
Bioavailability (F)
o This is why Penicillin G
is given by IM or IV
injections
Figure 18: Metabolism by
the Stomach and Intestines
(2) Enzymatic Metabolism
On oral administration of Insulin, it is broken down by
proteases which are released from
the pancreas, and this leaves the
insulin molecule ineffective and
decreases the amount of insulin that
passes into the bloodstream → (↓)
Bioavailability (F)
o This is why Insulin is given by
IV or SC injections
Figure 19: Enzymatic Metabolism
Figure 17: Effect of drug solubility on its bioavailability
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(C) FIRST-PASS EFFECT
(1) First-pass metabolism in the Liver
(2) Other routes of administration
On oral administration of the drug, after passing through
the GIT layers and environments that have been
mentioned, it then passes through the portal circulation to
the liver.
o By the time it reaches the liver, only 90% of the active
drug is remaining.
Generally, drugs that are not taken orally, do not go
through the first-pass effect
Rectally-administered drugs: small portion of the drug
may get into the portal system and go through the firstpass effect
The liver is considered the site of first-pass metabolism,
where the liver metabolizes the drug to such an extent
that the bioavailability is drastically reduced.
o Only about 30% of the drug gets to pass to the
bloodstream and be distributed to the tissues.
(Note: the bioavailability values are approximate and not
accurate)
E.g., Nitroglycerin, a drug that is used for anginal chest
pain patients.
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VI) REVIEW QUESTIONS
1) 18-year-old female brought to ED due to drug
overdose. Which route is most desirable for
administering the antidote?
a) IM
b) IV
c) Oral
d) SC
VII) REFERENCES
● UpToDate 2022
2) Drug A is a weakly basic drug with a pKA of 7.8. If
administered orally, at which of the following sites of
absorption will the drug be able to readily pass
through the membrane?
a) Mouth (pH 7.0)
b) Stomach (pH 2.5)
c) Duodenum (pH 6.1)
d) Jejunum (pH 8.0)
e) Ileum (pH 7.0)
3) Which mechanism of transport requires ATP to move
the molecule across the cell membrane?
a) Passive diffusion
b) Facilitated diffusion
c) Active transport
d) Endocytosis
4) Which of the following drugs would have the highest
bioavailability based on its administration route?
a) Penicillin G taken orally
b) Nitroglycerin taken orally
c) Insulin taken intravenously
d) Vitamin B12 taken orally
5) Which of the following routes has a 100%
bioavailability?
a) Intramuscular
b) Subcutaneous
c) Oral
d) Intravenous
e) Sublingual
6) Which is the best place for the absorption of weak
acid drugs?
a) Stomach
b) Proximal duodenum
c) Distal Duodenum
d) Distal ileum
7) How can weak bases be absorbed in the GI tract?
e) ↓ protons to ↑ B
f) ↓ protons to ↑ BH+
g) ↑ protons to ↑ B
h) ↑ protons ↓ BH+
8) Why does absorption of drugs decrease in shock states?
i) There is a reduced surface area of the GIT
j) There is reduced blood perfusion to the organs that
absorb the drugs
k) Contact time of the drug to the GIT cells is reduced
l) Shock patients have P-glycoproteins in the cell
membrane which inhibit absorption of drugs.
9) What is the result of P-Glycoprotein action in the GI
system?
m) Multidrug resistance
n) Inflammatory Bowel Disease
o) Decreased Total Surface Area
p) Decrease contact time
10) What is the formula to determine bioavailability of a
drug?
q) F = AUC IV / AUC oral
r) F = AUC IV x AUC oral
s) F = AUC oral / AUC IV
t) F = [Oral Dose] / AUC IV
Pharmacokinetics | Drug Absorption
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