Absorption of drugs:mechanism and factors affecting
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.
Bioavailability is the fraction of an ingested dose of a drug that is absorbed into the systemic circulation, compared with the same dose of the compound injected intravenously, which is directly injected into the systemic circulation. Bioavailability of a drug is determined during new product development.
Bioequivalence, on the other hand, is a comparison of relative bioavailability of two dosage forms in terms of the rate and extent of the drug levels achieved in the systemic circulation and the maximum drug concentration reached. Generic drugs are required to satisfy statistical criteria of bioe quiv alence to the branded version before they can be considered equivalent.
In the case of oral dosage forms, drug bioavailability depends on the rate and extent of drug absorption from the GI tract. Drug absorption from the gut depends on many factors, such as the drug’s solubility and intrinsic dissolution rate in the GI fluids, which are influenced by GI pH and motility, and the drug’s particle size and surface area. Thus, an interplay of physicochemical properties of the drug and physiological properties of the GI tract determines the outcome of factors that determine drug absorption.
Depending on their chemical properties, drugs may be absorbed from the GI tract by passive diffusion, facilitated diffusion, active transport, or endocytosis.
The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments. In other words, 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 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 their solubility in the membrane lipid bilayers.
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 and moving them from an area of high concentration to an area of low concentration. 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.
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 specific carrier proteins.
Energy-dependent active transport is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher drug concentration. The process is saturable. Active transport systems are selective and may be competitively inhibited by other co-transported substances.
Endocytosis and 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.
Factors influencing absorption
Effect of pH on drug absorption: Most drugs are either weak acids or weak bases. The effective concentration of the permeable form of each drug at itsabsorption site is determined by the relative concentrations of thecharged and uncharged forms. The ratio between the two formsis, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base.
Blood flow to the absorption site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach. [Note: Shock severely reduces blood flow to cutaneous tissues, thereby minimizing absorption from SC administration.]
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.
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 of the drug.
[Note: 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.] That is, it “pumps” drugs out of the 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.