Absorption of Drugs

✔ Absorption is the transfer of a drug from the site of administration to the bloodstream.
✔ The rate and extent of absorption depend on the environment where the drug is absorbed,
chemical characteristics of the drug, and the route of administration (which influences
bioavailability).
✔ Routes of administration other than intravenous may result in partial absorption and lower
bioavailability.

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 Mechanisms of absorption of drugs from
the GI tract
Depending on their chemical properties, drugs may be absorbed from the GI tract by :
• passive diffusion
• facilitated diffusion
• active transport
• endocytosis

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 Passive Diffusion
✔ The driving force for passive diffusion of a drug is the concentration gradient across a
membrane separating two body compartments.
✔ In other words, the drug moves from an area of high concentration to one of lower concentration.
✔ Passive diffusion does not involve a carrier, is not saturable, and shows low structural specificity.
✔ The vast majority of drugs are absorbed by this mechanism.
✔ Water-soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas
lipid-soluble drugs readily move across most biologic membranes due to solubility in the
membrane lipid bilayers.

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Facilitated diffusion

✔ Other agents can enter the cell through specialized transmembrane carrier proteins that
facilitate the passage of large molecules.
✔ These carrier proteins undergo conformational changes, allowing the passage of drugs or
endogenous molecules into the interior of cells.
✔ This process is known as facilitated diffusion. It does not require energy, can be
saturated, and may be inhibited by compounds that compete for the carrier

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 Active transport
✔ This mode of drug entry also involves specific carrier proteins that span the membrane.
✔ However, active transport is energy dependent, driven by the hydrolysis of adenosine triphosphate (ATP).
✔ It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of
higher concentration.
✔ The process is saturable.
✔ Active transport systems are selective and may be competitively inhibited by other cotransported
substances.

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Endocytosis & exocytosis
✔ This type of absorption is used to transport drugs of exceptionally large size across the cell membrane.
✔ Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off
the drug-filled vesicle. Exocytosis is the reverse of endocytosis.
✔ Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle
formation.
✔ Vitamin B12 is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for
example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and released by
exocytosis.

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Factors influencing absorption
1) Effect of pH on drug absorption
2) Blood flow to the absorption site
3) Total surface area available for absorption
4) Contact time at the absorption surface
5) Expression of P-glycoprotein

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 Effect of pH on drug absorption
• Most drugs are either weak acids or weak bases.\
• Acidic drugs (HA) release a proton (H+), causing a charged anion (A−) to form

• Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and
loss of a proton produces the uncharged base (B)

• A drug passes through membranes more readily if it is uncharged

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Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined
by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn,
determined by the pH at the site of absorption and by the strength of the weak acid or base, which is
represented by the ionization constant, pKa

The pKa is a measure of the strength of the interaction of a compound with a proton. The lower the pKa of a
drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug. Distribution equilibrium
is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces.

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Blood flow to the absorption site
The intestines receive much more blood flow than does the
stomach, so absorption from the intestine is favored over
the stomach.

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Total surface area available for
absorption
With a surface rich in brush borders containing microvilli,
the intestine has a surface area about 1000-fold that of the
stomach, making absorption of the drug across the
intestine more efficient.

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Contact time at the absorption surface

✔ If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not
well absorbed.
✔ Conversely, anything that delays the transport of the drug from the stomach to the intestine
delays the rate of absorption.
✔ The presence of food in the stomach both dilutes the drug and slows gastric emptying.
Therefore, a drug taken with a meal is generally absorbed more slowly.

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Expression of P-glycoprotein
P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules,
including drugs, across cell membranes.
It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain
capillaries, and is involved in transportation of drugs from tissues to blood.
That is, it “pumps” drugs out of cells.
Thus, in areas of high expression, P-glycoprotein reduces drug absorption. In addition to transporting many
drugs out of cells, it is also associated with multidrug resistance.

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BIOAVAILABILITY

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Bioavailability is the rate and extent to which an administered drug reaches the systemic
circulation. For example, if 100 mg of a drug is administered orally and 70 mg is absorbed
unchanged, the bioavailability is 0.7 or 70%. Determining bioavailability is important for
calculating drug dosages for nonintravenous routes of administration.

Bioavailability is determined by comparing plasma levels of a drug after a particular route of

In contrast to IV administration, which confers 100% bioavailability, orally administered drugs often undergo
firstpass metabolism. This biotransformation, in addition to chemical and physical characteristics of the drug,
determines the rate and extent to which the agent reaches the systemic circulation.
First-pass hepatic metabolism
When a drug is absorbed from the GI tract, it enters the portal circulation before entering the systemic
circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the
amount of unchanged drug entering the systemic circulation is decreased. This is referred to as first-pass
metabolism.

First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. For example,
more than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is primarily
administered via the sublingual, transdermal, or intravenous route. Drugs with high first-pass metabolism
should be given in doses sufficient to ensure that enough active drug reaches the desired site of action.

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Solubility of the drug
Very hydrophilic drugs are poorly absorbed because of the inability to cross lipid-rich cell
membranes.
Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they
are insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of
cells
For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in
aqueous solutions. This is one reason why many drugs are either weak acids or weak bases.

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Chemical instability
Some drugs, such as penicillin G, are unstable in the pH of
gastric contents. Others, such as insulin, are destroyed in
the GI tract by degradative enzymes.

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Nature of the drug formulation
Drug absorption may be altered by factors unrelated to the chemistry of
the drug. For example, particle size, salt form, crystal polymorphism,
enteric coatings, and the presence of excipients (such as binders and
dispersing agents) can influence the ease of dissolution and, therefore,
alter the rate of absorption.

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Bioequivalence and other
types of equivalence

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Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to
achieve peak blood concentrations. Two drug formulations are therapeutically equivalent if they are
pharmaceutically equivalent (that is, they have the same dosage form, contain the same active
ingredient at the same strength, and use the same route of administration) with similar clinical and
safety profiles. Thus, therapeutic equivalence requires that drug products are bioequivalent and
pharmaceutically equivalent