Lecture 1. Absorption
Oral Swallowed by mouth
Intravenous Injected in the bloodstream (e.g. chemotherapy)
Subcutaneous Injected under the skin (e.g. insulin)
Transdermal Transported through the skin by a patch
Topical Via solution applied on the skin
Intramuscular Injected into the muscle (e.g. vaccins)
Epidural Injected in the epidural space inside the bone
Suppository Placed in the rectum
Intranasal Nose spray
Buccal A tablet inside the mouth between cheek and gum until dissolved
Sublingual Tablet held underneath the tongue until dissolved
Intraperitoneal Injected within the peritoneal (abdominal) cavity
There are different types of administration of drugs to the body. These administrations can be systemic
or topical. Topical administration (like topical to the skin, ocular, optic, vaginal, respiratory, and nasal)
only causes local exposure, while systemic administration (like oral, rectal, or sublingual) causes the
whole circulatory system to be exposed. Systemic administration can be via enternal or paternal routes.
Parental routes avoid the gastrointestinal tract, GIT. Examples are subcutaneous (small volumes, and
slow absorption via passive diffusion), intravenous (high concentrations, fast therapeutic effect, and
100% bioavailability), intramuscular (slower absorption due to more adipose tissue, but this differs
because there are differences in adipose tissue in people), or special cases like intracardiac. Enternal
routes do pass the GIT. Oral route is than usually first choice. Absorption is dependent in part of the
physiological state of GIT and the physicochemical properties of the drug. The physiological processes
in the GIT involve secretion, digestion, and absorption.
All these different types of
administration have a different impact in
how fast it will enter the bloodstream.
This figure shows that intravenous is the
most effective administration way. For
oral administration, the effectiveness is
much lower because of first pass
excretion due to lack of absorption. To
choose a way of administrating a drug,
the bioavailability is compared to
intravenous drugs.
To overcome biological barriers, the drug
must be released from a pharmaceutical
carrier, and be in its free form (Liberation-ADME, or L-ADME). Some dosage form may already contain
drug in solution. Absorption will therefore depend on the (1) physiochemical properties of drugs
(aqueous solubility, ionization constant, permeability to barrier, molecular size and lipophilicity), (2)
anatomical and physiological properties of site of absorption (pH, presence of drug transporters, tight
junctions composition), and (3) administration environment (e.g. for oral drugs: before or after a meal).
1
,Gastrointestinal tract (GIT)
In the GIT, there are different pH values in each section, there are different types of digestion enzymes
present, and there are variations in mucus composition (important for drug dissolution).
The small intestine consists of the Duodenum, Jejunum,
and Ileum. In the small intestine the pH is higher (more
basic) than in the stomach. The further you go in in the
small intestine, the higher the pH. The transit time is the
time available for absorption. Majority of pancreas
enzymes added to the duodenum are proteases that
hydrolyse drugs that contain hydrolysable functional
groups. Pro-drugs are designed to take advantage of
hydrolysis, because this causes it to be in its biologically
active state. After eating fatty foods, the gallbladder
releases bile acids into the small intestine. This makes
sure the fatty foods are dissolves properly.
A large surface is important for absorption. The GIT has a length of 5 m consisting of mucosal folds
(plicae), intestinal villi, microvilli on apical surface of cells that cause a large surface for absorption. Main
cells involved in absorption are enterocytes (epithelial cells).
Absorption, and transporters
Drug absorption in the GIT can happen in different ways: (1) trans- or paracellular passive diffusion, (2)
active transport, and (3) endocytosis. In order to transport drugs through cellmembranes, the drug
needs to be in solution (except for endocytosis). The solubility of a drug depends on the solvent,
temperature, and pH. The permeability of a drug depends on whether passive diffusion, active transport
or a combination is able to happen. Lipophilic drugs have low aqueous solubility but high membrane
permeability. Ionized drugs usually more soluble in water, but non-ionized drugs easier absorbed by
passive diffusion. Because the pH in small intestine ranges between 5 and 8, drugs that are weak bases
will be absorbed easier due to predominance in non-ionized form. Acids will most likely form ionized
forms.
Cell membranes consists of phospholipids. These phospholipids contain two hydrophobic fatty acid tails
and one hydrophilic head. These phospholipids are arranged in a fluid bilayer. The phosphate groups
are in contact with the aqueous phase, and the fatty acid in the inner space. The arrangement of the
cell membrane in principal allows free lateral diffusion, permeable to small, non-polar molecules, and
difficult to pass for large compounds with high polarity. Membrane proteins consist of a high amount of
α-helices and are important for absorption.
2
, Cellular uptake of compounds
Simple Simple membrane diffusion happens direction via the cell membrane, no
membrane membrane proteins are involved, and it goes down the concentration gradient.
diffusion 𝑑𝑄 𝑑𝐶
=𝐷×𝑃×𝑆×
𝑑𝑡 𝑑𝑥
The kinetics of simple diffusion follows Fick’s
first law in which Q is the amount of drug, dt
is the time period, D is the diffusion
coefficient, P is the patrician coefficient of
𝑑𝐶
the drug, S is the surface, and 𝑑𝑥 is the
concentration gradient. Following Fick’s first
law, the flux proportional to the concentration gradient, and causes a linear, and
non-saturable process.
Facilitated 𝑑𝐴 𝑉 ×𝐴
𝑑𝑡
= 𝐾𝑚 +𝐴
diffusion 𝑚
(in first order kinetics, the A (concentration substrate) in the denominator of the
(passive-
formula can be neglected)
mediated
transport)
Facilitated diffusion follows the Michaelis Menten
saturation curve. This is a saturated process that
depends on the number of channels or carriers per
cell. Because most drugs are either weak acids or
weak bases, the absorption will depend highly on the
pH at absorption site because charged drugs are less
permeable.
Paracellular Paracellular transport goes via tight junctions:
transport occluding, and claudins. Expression of these
tight junctions depends on the tissue (e.g. BBB
very tight, kidney/gut more leaky).
Active transport Carrier proteins move substances across the membrane but require energy (direct
or indirect). (1) Primary active transport requires ATP to transport against
concentration gradients. (2) In secondary active transport move couples of ions
(typically 𝑁𝑎+ or 𝐻 + ) down its electrochemical gradient (symport or antiport)
with movement of molecules against a concentration /electrochemical gradient.
In practice, a combination between active transport and diffusion might occur of
absorption.
There is a difference between uptake transporters and efflux transporters. Uptake
transporters collaborate with absorption, and have a narrow substrate specificity,
while efflux transporters oppose with absorption, and have a wide substrate
specificity.
Endocytosis, or
Transcytosis
3
, Main classes of transporters involved in
absorption and efflux of drugs
o ATP-binding cassette (ABC)
transporter: These transporters
are exporters, and play a role in
primary active transports. The
transporter exists of a
transmembrane domains
(TMD), and two nucleotide-
binding domains (NBD). The NBD binds two ATP’s
that causes a conformational change to open the
pathway to a drug molecule. The name of an ABC
transporter is often due to a discovery in cancer,
but is also expressed in normal tissue. One
important ABC transporter is P-glycoprotein (Pgp).
The set of substrates of Pgp and CYP3A4 partially
overlap.
o Solute carrier (SLC) transporter = This transporter
is secondary active and allows substrates to flow
uphill against electrochemical gradient by coupling to solute transport. The most relevant SLC
carriers are SLC22 family, like OAT (anion transporter), and OCT (cation transporter).
Uptake transporters in the GIT tract enhance the absorption of some drug molecules and have an impact
on pharmacokinetics. They enhance the distribution to certain organs (e.g. kidney). Efflux transporter
(apical/luminal side) of enterocytes (epithelial cells on the inner surface of the small and large intestines)
opposes (try to prevent) the distribution of some drugs but usually oral dosing is high and efflux
transporters are saturated. Efflux transporter may regulate the rate of uptake so that CYPP450
substrates are not saturated.
4
Oral Swallowed by mouth
Intravenous Injected in the bloodstream (e.g. chemotherapy)
Subcutaneous Injected under the skin (e.g. insulin)
Transdermal Transported through the skin by a patch
Topical Via solution applied on the skin
Intramuscular Injected into the muscle (e.g. vaccins)
Epidural Injected in the epidural space inside the bone
Suppository Placed in the rectum
Intranasal Nose spray
Buccal A tablet inside the mouth between cheek and gum until dissolved
Sublingual Tablet held underneath the tongue until dissolved
Intraperitoneal Injected within the peritoneal (abdominal) cavity
There are different types of administration of drugs to the body. These administrations can be systemic
or topical. Topical administration (like topical to the skin, ocular, optic, vaginal, respiratory, and nasal)
only causes local exposure, while systemic administration (like oral, rectal, or sublingual) causes the
whole circulatory system to be exposed. Systemic administration can be via enternal or paternal routes.
Parental routes avoid the gastrointestinal tract, GIT. Examples are subcutaneous (small volumes, and
slow absorption via passive diffusion), intravenous (high concentrations, fast therapeutic effect, and
100% bioavailability), intramuscular (slower absorption due to more adipose tissue, but this differs
because there are differences in adipose tissue in people), or special cases like intracardiac. Enternal
routes do pass the GIT. Oral route is than usually first choice. Absorption is dependent in part of the
physiological state of GIT and the physicochemical properties of the drug. The physiological processes
in the GIT involve secretion, digestion, and absorption.
All these different types of
administration have a different impact in
how fast it will enter the bloodstream.
This figure shows that intravenous is the
most effective administration way. For
oral administration, the effectiveness is
much lower because of first pass
excretion due to lack of absorption. To
choose a way of administrating a drug,
the bioavailability is compared to
intravenous drugs.
To overcome biological barriers, the drug
must be released from a pharmaceutical
carrier, and be in its free form (Liberation-ADME, or L-ADME). Some dosage form may already contain
drug in solution. Absorption will therefore depend on the (1) physiochemical properties of drugs
(aqueous solubility, ionization constant, permeability to barrier, molecular size and lipophilicity), (2)
anatomical and physiological properties of site of absorption (pH, presence of drug transporters, tight
junctions composition), and (3) administration environment (e.g. for oral drugs: before or after a meal).
1
,Gastrointestinal tract (GIT)
In the GIT, there are different pH values in each section, there are different types of digestion enzymes
present, and there are variations in mucus composition (important for drug dissolution).
The small intestine consists of the Duodenum, Jejunum,
and Ileum. In the small intestine the pH is higher (more
basic) than in the stomach. The further you go in in the
small intestine, the higher the pH. The transit time is the
time available for absorption. Majority of pancreas
enzymes added to the duodenum are proteases that
hydrolyse drugs that contain hydrolysable functional
groups. Pro-drugs are designed to take advantage of
hydrolysis, because this causes it to be in its biologically
active state. After eating fatty foods, the gallbladder
releases bile acids into the small intestine. This makes
sure the fatty foods are dissolves properly.
A large surface is important for absorption. The GIT has a length of 5 m consisting of mucosal folds
(plicae), intestinal villi, microvilli on apical surface of cells that cause a large surface for absorption. Main
cells involved in absorption are enterocytes (epithelial cells).
Absorption, and transporters
Drug absorption in the GIT can happen in different ways: (1) trans- or paracellular passive diffusion, (2)
active transport, and (3) endocytosis. In order to transport drugs through cellmembranes, the drug
needs to be in solution (except for endocytosis). The solubility of a drug depends on the solvent,
temperature, and pH. The permeability of a drug depends on whether passive diffusion, active transport
or a combination is able to happen. Lipophilic drugs have low aqueous solubility but high membrane
permeability. Ionized drugs usually more soluble in water, but non-ionized drugs easier absorbed by
passive diffusion. Because the pH in small intestine ranges between 5 and 8, drugs that are weak bases
will be absorbed easier due to predominance in non-ionized form. Acids will most likely form ionized
forms.
Cell membranes consists of phospholipids. These phospholipids contain two hydrophobic fatty acid tails
and one hydrophilic head. These phospholipids are arranged in a fluid bilayer. The phosphate groups
are in contact with the aqueous phase, and the fatty acid in the inner space. The arrangement of the
cell membrane in principal allows free lateral diffusion, permeable to small, non-polar molecules, and
difficult to pass for large compounds with high polarity. Membrane proteins consist of a high amount of
α-helices and are important for absorption.
2
, Cellular uptake of compounds
Simple Simple membrane diffusion happens direction via the cell membrane, no
membrane membrane proteins are involved, and it goes down the concentration gradient.
diffusion 𝑑𝑄 𝑑𝐶
=𝐷×𝑃×𝑆×
𝑑𝑡 𝑑𝑥
The kinetics of simple diffusion follows Fick’s
first law in which Q is the amount of drug, dt
is the time period, D is the diffusion
coefficient, P is the patrician coefficient of
𝑑𝐶
the drug, S is the surface, and 𝑑𝑥 is the
concentration gradient. Following Fick’s first
law, the flux proportional to the concentration gradient, and causes a linear, and
non-saturable process.
Facilitated 𝑑𝐴 𝑉 ×𝐴
𝑑𝑡
= 𝐾𝑚 +𝐴
diffusion 𝑚
(in first order kinetics, the A (concentration substrate) in the denominator of the
(passive-
formula can be neglected)
mediated
transport)
Facilitated diffusion follows the Michaelis Menten
saturation curve. This is a saturated process that
depends on the number of channels or carriers per
cell. Because most drugs are either weak acids or
weak bases, the absorption will depend highly on the
pH at absorption site because charged drugs are less
permeable.
Paracellular Paracellular transport goes via tight junctions:
transport occluding, and claudins. Expression of these
tight junctions depends on the tissue (e.g. BBB
very tight, kidney/gut more leaky).
Active transport Carrier proteins move substances across the membrane but require energy (direct
or indirect). (1) Primary active transport requires ATP to transport against
concentration gradients. (2) In secondary active transport move couples of ions
(typically 𝑁𝑎+ or 𝐻 + ) down its electrochemical gradient (symport or antiport)
with movement of molecules against a concentration /electrochemical gradient.
In practice, a combination between active transport and diffusion might occur of
absorption.
There is a difference between uptake transporters and efflux transporters. Uptake
transporters collaborate with absorption, and have a narrow substrate specificity,
while efflux transporters oppose with absorption, and have a wide substrate
specificity.
Endocytosis, or
Transcytosis
3
, Main classes of transporters involved in
absorption and efflux of drugs
o ATP-binding cassette (ABC)
transporter: These transporters
are exporters, and play a role in
primary active transports. The
transporter exists of a
transmembrane domains
(TMD), and two nucleotide-
binding domains (NBD). The NBD binds two ATP’s
that causes a conformational change to open the
pathway to a drug molecule. The name of an ABC
transporter is often due to a discovery in cancer,
but is also expressed in normal tissue. One
important ABC transporter is P-glycoprotein (Pgp).
The set of substrates of Pgp and CYP3A4 partially
overlap.
o Solute carrier (SLC) transporter = This transporter
is secondary active and allows substrates to flow
uphill against electrochemical gradient by coupling to solute transport. The most relevant SLC
carriers are SLC22 family, like OAT (anion transporter), and OCT (cation transporter).
Uptake transporters in the GIT tract enhance the absorption of some drug molecules and have an impact
on pharmacokinetics. They enhance the distribution to certain organs (e.g. kidney). Efflux transporter
(apical/luminal side) of enterocytes (epithelial cells on the inner surface of the small and large intestines)
opposes (try to prevent) the distribution of some drugs but usually oral dosing is high and efflux
transporters are saturated. Efflux transporter may regulate the rate of uptake so that CYPP450
substrates are not saturated.
4
