Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the route of administration. For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation. Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. For example, the oral route requires that a drug dissolve in the GI fluid and then penetrate the epithelial cells of the intestinal mucosa, yet disease states or the presence of food may affect this process.
A. Transport of a drug from the GI tract
Depending on their chemical properties, drugs may be absorbed from the GI tract by either passive diffusion or active transport.
1. Passive diffusion:
The driving force for passive absorption of a drug is the concentration gradient across a membrane
separating two body compartments; that is, the drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs gain access to the body by this mechanism. Lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane bilayers. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores
(Figure : schematic relation ship of drug crossing the cell memberain of epithelial ce of gastrointestinal tract
ADP: adinosin di phosphate ).
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, moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. This type of diffusion does not require energy, can be saturated, and may be inhibited.
2. Active transport:
This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs
that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using these specific carrier proteins. Active transport is energy-dependent and is driven by the hydrolysis of adenosine triphosphate . It is capable of moving drugs against a concentration gradient that is, from a region of low drug concentration to one of higher drug concentration. The process shows saturation kinetics for the carrier, much in the same way that an enzyme-catalyzed reaction shows a maximal velocity at high substrate levels where all the active sites are filled with substrate.
3. Endocytosis and exocytosis:
This type of drug delivery transports drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. Exocytosis is the reverse of endocytosis and is used by cells to secrete many
B. Effect of pH on drug absorption
Most drugs are either weak acids or weak bases. Acidic drugs (HA) release an H Weak bases (BH + ) can also release an H + causing a charged anion (A-) to form
. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B):
1. Passage of an uncharged drug through a membrane:
A drug passes through membranes more readily if it is uncharged .
figure :A. diffusion of non ionized form of a weak acid through a lipid membrane .
B. diffusion of non ionized form of a weak base through a lipid membrane .
Thus, for a weak acid, the uncharged HA can permeate through membranes, and A
cannot. For a weak base, the uncharged form, B, penetrates through the cell membrane, but BH + does not. 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 pK a
(Figure: The distribution of a drug between its ionized and non-ionized forms depends on the ambient pH and pKa of the drug. For illustrative purposes, the drug has been assigned a pK a of 6.5.).
[Note: The pK is a measure of the strength of the interaction of a compound with a proton. The lower the pKa-a of a drug, the more acidic it is. Conversely, the higher the pK, 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. [Note: Highly lipid-soluble drugs rapidly cross membranes and a often enter tissues at a rate determined by blood flow.] - ) to form: 2
2. Determination of how much drug will be found on either side of a membrane: The relationship of pK
and the ratio of
acid-base concentrations to pH is expressed by the Henderson-Hasselbalch equation:
This equation is useful in determining how much drug will be found on either side of a membrane that separates two compartments that differ in pHâ€”for example, stomach (pH 1.0-1.5) and blood plasma (pH 7.4). [Note: The lipid solubility of the non-ionized drug directly determines its rate of equilibration.]
C. Physical factors influencing absorption
1. Blood flow to the absorption site:
Blood flow to the intestine is much greater than the flow to the stomach; thus,absorption from the intestine is favored over that from the stomach. [Note: Shock severely reduces blood flow to
cutaneous tissues, thus minimizing the absorption from SC administration.]
2. Total surface area available for absorption:
Because the intestine has a surface rich in microvilli, it has a surface area about 1000-fold that of the stomach; thus, absorption of the drug across the intestine is more efficient.
3. Contact time at the absorption surface:
If a drug moves through the GI tract very quickly, as in 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 of the drug.
[Note: Parasympathetic input increases the rate of gastric emptying, whereas sympathetic input (prompted, for example, by exercise or stressful emotions), as well as anticholinergics (for example, dicyclomine), prolongs gastric emptying. Also, 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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