Drug Absorption Barriers

Section Index

1). Routes of Drug Administration:

Injection
Oral/Buccal
Transdermal/Topical
Ocular
Pulmonary/Nasal
Rectal/vaginal
Most drugs have to reach targets that are not near the site of administration. Therefore-if, how, and how much a drug is absorbed will ultimately determine whether the drug is effective and sometimes how long it stays effective. Simply stated, there are tens of thousands of molecules that will kill the AIDS virus in test tubes, but few of those will become drugs because many of them cannot cross various barriers in vivo (including both physical and metabolic).

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2). In Vivo Drug Delivery Vehicles

Systemic circulation
Lymphatic circulation
To reach target sites, drugs have to be carried from the administration site to the action site. Following absorption, the most important in vivo delivery vehicle for the majority of drugs is the systemic circulation. Other drugs may rely on lymph vessels for distribution. Some may use both. Although the systemic circulation and the lymphatic system are generally efficient in carrying drug molecules, it is often difficult to get the molecules there. The lack of proper absorption is the main reason why we have a lot of injectables on the market.

Question: What are the other reasons that injectables are marketed?

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3). Absorption Pathways

Transcellular: passive and carrier-mediated (active and facilitated)
Paracellular

There are two generic processes of drug absorption across barrier membranes (e.g., epithelial membrane). The first type is called "the transcellular transport process," where drug molecules have to go through the barrier cells (e.g. epithelial cells), to reach the systemic circulation. Transcellular transport is typically a two step process, starting with drug uptake into the cells, and ending with drug efflux out of the cells. The second type is called "the paracellular transport process," where the drug molecules travel between the cells (or in the gaps) to reach the systemic circulation.
The transcellular transport route is generally the most important route for drug absorption, except in transdermal drug delivery, where paracellular transport is the most important. However, it is possible that both routes contribute to the absorption of a particular drug.
The main barrier to drug absorption through these routes is the epithelial membrane. The organization of epithelial cells is essential to the epithelium's function as an effective barrier. Without organizational structures such as tight junctions, the individual epithelial cell cannot function as a barrier because drug molecules will simply travel between the cells to reach systemic circulation. Here, the sum is MUCH more important than the parts.

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4). Plasma Membrane

Lipid bilayer
Transport proteins
Metabolic enzymes
Pharmacological receptors

To discuss the organization of various epithelia, it is helpful to first examine the structure of epithelial cells. The most important structure of an epithelial cell, as related to drug transport, is its cellular membrane since it is the main structure for cell protection and the main barrier to drug absorption. The structure of the cellular plasma membrane is best represented by a lipid bilayer model. (Note: not all epithelial cells are alike and have this structure. Stratified epithelial cells, for example, do not have this structure since they are keratinized.)

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5). Epithelial Cells

1. Function: Protective, absorptive, secretory.

2. Classification:

Simple squamous - blood vessel, lung epithelium
Simple columnar - intestinal epithelium
Stratified squamous - oral mucosa
Pseudostratified ciliated columnar - respiratory passages

Survey of several epithelial cells are presented below.

3. Characteristics:

Polarized
- membrane composition
- enzyme distribution
- transport protein distribution (e.g., amino acid and glucose carriers)
Connective
- simple squamous: Less leaky than the connective and fat tissue, but leakiest among the four discussed here.
- simple columnar: Tight to very tight, and drugs with MW>4,000 cannot cross.
- stratified squamous: Physically strong, and very tight.
- Pseudostratified ciliated columnar: Tight. Cilia-rich.
Rapid Turnover
- stomach cells: 5 x 10⁵ cells/minute turnover rate
- intestinal cells: 14 day life cycle and 4-7 functional life span as absorptive cells.

4. Epithelial Membrane (Review your anatomy and physiology book for examples. Alternatively, refer to "Physiological Pharmaceutics" for more examples.

Different structures
Different types of cells
Differentiation process
Organization

These important points should be gained from this section:

There are a variety of epithelial structures.
The epithelial cells typically undergo a maturation process through differentiation.
Other cells may co-exist with these epithelial cells in the epithelium.

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Cell Junctions

1) Classification:

tight junction (TJ)
desmosome (D)
gap junction (GJ)

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2) Functions:

Maintain barrier properties - TJ
Communicate cellular information - GJ
Share nutrients - GJ
Keep cells together - D
Maintain the polarity of epithelium - TJ

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3) Tight Junction (TJ is the most important cellular junction in drug absorption.)

TJs are formed when specific proteins in two interacting plasma membranes make direct contact across the intercellular space. The TJ is one of the most important morphological and functional characteristics of the epithelial membrane. A TJ is considered an essential feature of the epithelial membrane. Without it, the cells can diffuse, and membrane polarity and composition can change. TJ also functions to seal the neighboring cells together to create a continuous sheet of cells which restricts the free movement of molecules, even those that are relatively small (e.g., mannitol which has a molecular weight of 182).

Some of the characteristics of TJ are:

It is linearly stranded with a belt-like protein chain.
It has a gap of less than 2 Å (1 Å=10^-8 cm) (As a comparison, the diameter of the hair is about 70 mm or 7 x 10⁵ Å.)
The protein chains are held together by Ca⁺⁺ /Mg⁺⁺. Use of chelating agents, such as EDTA can significantly reduce the barrier properties of the epithelial membrane (Fig.2.1).
A six-pack of beer represents the best possible analogy to the organization of TJ. However, the epithelial barrier is absolutely permeable to alcohol.

Fig.2.1 Effect of EDTA on mannitol transport across Caco-2 cell monolayer.

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4) Gap Junction (GJ)

The GJ is not a unique characteristic of epithelial cells, but all epithelial cells have it.

Characteristics:

It has a gap size of 2-3 nm or 10 times larger than TJ.
It serves as a linkage between the cells.
It is regulated by Ca⁺⁺, a high concentration of Ca⁺⁺ can decrease the size of GJ.

Functions:

Cellular communication
Nutrient exchange

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5) Desmosome

Functions:
Holding cells together.
Connecting neighboring cells.
Anchoring cells to the basement membrane.
Anchoring sites for the keratin filaments and provide structural framework for cytoplasmic components.

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Absorption or Transport or Diffusion: Which one is the correct terminology?

In this class, we use the words "absorption," "diffusion," or "transport" interchangeably because they are not always distinguishable from the study design. The word "transport" in this class means molecular movement/travel with or without additional vehicles. These terminologies are also used frequently in published literatures.

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Drug Delivery and Epithelial Membrane

Cell Junctions

Self-Evaluation Questions