Absorption (Pharmacokinetics)
Encyclopedia
In pharmacology
(and more specifically pharmacokinetics
), absorption is the movement of a drug into the bloodstream.
Absorption involves several phases. First, the drug needs to be introduced via some route of administration
(oral
, via the skin
, etc.) and in a specific dosage form
such as a tablet
, capsule, and so on.
In other situations, such as intravenous therapy
, intramuscular injection
, enteral nutrition
and others, absorption is even more straightforward and there is less variability in absorption and bioavailability
is often near 100%. It is considered that intravascular administration (e.g. IV) does not involve absorption, and there is no loss of drug. So, the fastest route of absorption is inhalation
, and not as mistakenly considered the intravenous administration.
Absorption is a primary focus in drug development
and medicinal chemistry
, since the drug must be absorbed before any medicinal effects can take place. Moreover, the drug's pharmacokinetic profile can be easily and significantly changed by adjusting factors that affect absorption.
to the stomach
. Because the stomach is an aqueous environment, this is the first place where a tablet may dissolve
.
The rate of dissolution is a key target for controlling the duration of a drug's effect, and as such, several dosage forms that contain the same active ingredient may be available, differing only in the rate of dissolution. If a drug is supplied in a form that is not readily dissolved, the drug may be released more gradually over time with a longer duration of action. Having a longer duration of action may improve compliance
since the medication will not have to be taken as often. Additionally, slow-release dosage forms may maintain concentrations within an acceptable therapeutic range over a long period of time, as opposed to quick-release dosage forms which may result in sharper peaks and troughs in serum concentrations.
The rate of dissolution is described by the Noyes–Whitney equation as shown below:
Where:
As can be inferred by the Noyes-Whitney equation, the rate of dissolution may be modified primarily by altering the surface area of the solid. The surface area may be adjusted by altering the particle size (e.g. micronization). The rate of dissolution may also be altered by choosing a suitable polymorph
of a compound. Specifically, crystalline forms dissolve slower than amorphous forms.
Also, coatings on a tablet or a pellet may act as a barrier to reduce the rate of dissolution. Coating may also be used to modify where dissolution takes place. For example, enteric coating
s may be applied to a drug, so that the coating only dissolves in the basic
environment of the intestines. This will prevent release of the drug before reaching the intestines.
Since solutions are already dissolved, they do not need to undergo dissolution before being absorbed.
Lipid-soluble drugs are less absorbed than water-soluble drugs, especially when they are enteral.
is lined with epithelial cells
. Drugs must pass or permeate through these cells in order to be absorbed into the circulatory system
. One particular cellular barrier that may prevent absorption of a given drug is the cell membrane
. Cell membranes are essentially lipid bilayer
s which form a semipermeable membrane
. Pure lipid bilayers are generally permeable only to small, uncharged solutes. Hence, whether or not a molecule is ionized
will affect its absorption, since ionic molecules are charged. Solubility favors charged species, and permeability favors neutral species. It is the balance between these opposing properties that allow a molecule to dissolve, permeate and to be absorbed.
The Henderson-Hasselbalch equation
offers a way to determine the proportion of a substance that is ionized at a given pH. In the stomach, drugs that are weak acid
s (such as aspirin
) will be present mainly in their non-ionic form, and weak bases will be in their ionic form. Since non-ionic species diffuse more readily through cell membrane
s, weak acids will have a higher absorption in the highly acidic stomach
.
However, the reverse is true in the basic
environment of the intestines-- weak bases (such as caffeine
) will diffuse more readily since they will be non-ionic.
This aspect of absorption has been targeted by medicinal chemistry. For example, a suitable analog
may be chosen so that the drug is more likely to be in a non-ionic form. Also, prodrug
s of a compound may be developed by medicinal chemists-- these chemical variants may be more readily absorbed and then metabolized by the body into the active compound. However, changing the structure of a molecule is less predictable than altering dissolution properties, since changes in chemical structure may affect the pharmacodynamic properties of a drug.
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
(and more specifically pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
), absorption is the movement of a drug into the bloodstream.
Absorption involves several phases. First, the drug needs to be introduced via some route of administration
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
(oral
Mouth
The mouth is the first portion of the alimentary canal that receives food andsaliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth....
, via the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, etc.) and in a specific dosage form
Dosage form
-Introduction:Dosage forms are a mixture of active drug components and nondrug components. Depending on the method of administration they come in several types. These are liquid dosage form, solid dosage form and semisolid dosage forms. A Liquid dosage form is the liquid form of a dose of a...
such as a tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
, capsule, and so on.
In other situations, such as intravenous therapy
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
, intramuscular injection
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
, enteral nutrition
Nasogastric intubation
Nasogastric intubation is a medical process involving the insertion of a plastic tube through the nose, past the throat, and down into the stomach.-Uses:...
and others, absorption is even more straightforward and there is less variability in absorption and bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
is often near 100%. It is considered that intravascular administration (e.g. IV) does not involve absorption, and there is no loss of drug. So, the fastest route of absorption is inhalation
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....
, and not as mistakenly considered the intravenous administration.
Absorption is a primary focus in drug development
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
and medicinal chemistry
Medicinal chemistry
Medicinal chemistry and pharmaceutical chemistry are disciplines at the intersection of chemistry, especially synthetic organic chemistry, and pharmacology and various other biological specialties, where it is involved with design, chemical synthesis and development for market of pharmaceutical...
, since the drug must be absorbed before any medicinal effects can take place. Moreover, the drug's pharmacokinetic profile can be easily and significantly changed by adjusting factors that affect absorption.
Dissolution
In the most common situation, a tablet is ingested and passes through the esophagusEsophagus
The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...
to the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
. Because the stomach is an aqueous environment, this is the first place where a tablet may dissolve
Solvation
Solvation, also sometimes called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute...
.
The rate of dissolution is a key target for controlling the duration of a drug's effect, and as such, several dosage forms that contain the same active ingredient may be available, differing only in the rate of dissolution. If a drug is supplied in a form that is not readily dissolved, the drug may be released more gradually over time with a longer duration of action. Having a longer duration of action may improve compliance
Compliance (medicine)
In medicine, compliance describes the degree to which a patient correctly follows medical advice...
since the medication will not have to be taken as often. Additionally, slow-release dosage forms may maintain concentrations within an acceptable therapeutic range over a long period of time, as opposed to quick-release dosage forms which may result in sharper peaks and troughs in serum concentrations.
The rate of dissolution is described by the Noyes–Whitney equation as shown below:
Where:
is the rate of dissolution.- A is the surface areaSurface areaSurface area is the measure of how much exposed area a solid object has, expressed in square units. Mathematical description of the surface area is considerably more involved than the definition of arc length of a curve. For polyhedra the surface area is the sum of the areas of its faces...
of the solid. - C is the concentration of the solid in the bulk dissolution medium.
is the concentration of the solid in the diffusionDiffusionMolecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
layer surrounding the solid.- D is the diffusion coefficientCoefficientIn mathematics, a coefficient is a multiplicative factor in some term of an expression ; it is usually a number, but in any case does not involve any variables of the expression...
. - L is the diffusion layer thickness.
As can be inferred by the Noyes-Whitney equation, the rate of dissolution may be modified primarily by altering the surface area of the solid. The surface area may be adjusted by altering the particle size (e.g. micronization). The rate of dissolution may also be altered by choosing a suitable polymorph
Polymorphism (materials science)
Polymorphism in materials science is the ability of a solid material to exist in more than one form or crystal structure. Polymorphism can potentially be found in any crystalline material including polymers, minerals, and metals, and is related to allotropy, which refers to chemical elements...
of a compound. Specifically, crystalline forms dissolve slower than amorphous forms.
Also, coatings on a tablet or a pellet may act as a barrier to reduce the rate of dissolution. Coating may also be used to modify where dissolution takes place. For example, enteric coating
Enteric coating
An enteric coating is a barrier applied to oral medication that controls the location in the digestive system, where it is absorbed. Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.Most enteric coatings work by...
s may be applied to a drug, so that the coating only dissolves in the basic
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
environment of the intestines. This will prevent release of the drug before reaching the intestines.
Since solutions are already dissolved, they do not need to undergo dissolution before being absorbed.
Lipid-soluble drugs are less absorbed than water-soluble drugs, especially when they are enteral.
Ionization
The gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
is lined with epithelial cells
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. Drugs must pass or permeate through these cells in order to be absorbed into the circulatory system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
. One particular cellular barrier that may prevent absorption of a given drug is the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Cell membranes are essentially lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
s which form a semipermeable membrane
Semipermeable membrane
A semipermeable membrane, also termed a selectively permeable membrane, a partially permeable membrane or a differentially permeable membrane, is a membrane that will allow certain molecules or ions to pass through it by diffusion and occasionally specialized "facilitated diffusion".The rate of...
. Pure lipid bilayers are generally permeable only to small, uncharged solutes. Hence, whether or not a molecule is ionized
Ionization
Ionization is the process of converting an atom or molecule into an ion by adding or removing charged particles such as electrons or other ions. This is often confused with dissociation. A substance may dissociate without necessarily producing ions. As an example, the molecules of table sugar...
will affect its absorption, since ionic molecules are charged. Solubility favors charged species, and permeability favors neutral species. It is the balance between these opposing properties that allow a molecule to dissolve, permeate and to be absorbed.
The Henderson-Hasselbalch equation
Henderson-Hasselbalch equation
In chemistry, the Henderson–Hasselbalch equation describes the derivation of pH as a measure of acidity in biological and chemical systems...
offers a way to determine the proportion of a substance that is ionized at a given pH. In the stomach, drugs that are weak acid
Weak acid
A weak acid is an acid that dissociates incompletely. It does not release all of its hydrogens in a solution, donating only a partial amount of its protons to the solution...
s (such as aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
) will be present mainly in their non-ionic form, and weak bases will be in their ionic form. Since non-ionic species diffuse more readily through cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s, weak acids will have a higher absorption in the highly acidic stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
.
However, the reverse is true in the basic
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
environment of the intestines-- weak bases (such as caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
) will diffuse more readily since they will be non-ionic.
This aspect of absorption has been targeted by medicinal chemistry. For example, a suitable analog
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
may be chosen so that the drug is more likely to be in a non-ionic form. Also, prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
s of a compound may be developed by medicinal chemists-- these chemical variants may be more readily absorbed and then metabolized by the body into the active compound. However, changing the structure of a molecule is less predictable than altering dissolution properties, since changes in chemical structure may affect the pharmacodynamic properties of a drug.