Oral Drug Absorption Barrier
Oral drugs enter the gastrointestinal tract by mouth, and then undergo digestion and absorption in the gastrointestinal tract. Studies have shown that the gastrointestinal mucosa is attached to the gastrointestinal tract, which is a key barrier affecting the absorption of oral drugs. Studies have found that the gastrointestinal mucosa is covered with a 100-150gm thick aqueous mucosa layer secreted by goblet cells, which is the rate-limiting step for the drug to reach the surface of intestinal epithelial cells. Below the mucosal layer are columnar epithelial cells with tight junctions. In the cell layer there are intestinal epithelial cells, goblet cells, endocrine cells and Peyer’s cells. The epithelial cell layer faces the lumen of the gastrointestinal tract. The basal layer is located on the basolateral side of the epithelial cell layer and includes lymphatic vessels, smooth muscle cells, nerves and blood vessels. There are four pathways for drugs to penetrate the intestinal mucosal barrier: 1. Hydrophobic drugs mainly pass through the intestinal mucosa through a transcellular pathway; 2. Hydrophilic drugs cannot penetrate the cell membrane and must be transported through the cell bypass, but are tightly connected Restrictions; 3. Receptor-mediated drug ingestion passes through the intestinal mucosal channel; 4. The efflux pump on the intestinal mucosal cells discharges the drug through the cell membrane.
The physiological barrier of the gastrointestinal mucosa selectively passes certain molecules to prevent toxins, bacteria and viruses from invading from the top to the basal side. Intercellular junctions can be divided into three parts: tight junctions (closed zonules); adhesion junctions (adhesive zonules); desmosomes. The cell-to-cell connection is an 80nm long curved path formed between two adjacent cells, running through the entire side of the cell. The tight junction or closed zonule is at the top of most cells, and its function is to close adjacent cells tightly. Tight junctions cause cell surface polarization, produce barriers and limit the free diffusion of lipids and proteins from the top of the outer protoplasmic membrane to the basolateral surface. The intercellular permeability of the drug through the cell junction depends on the pore size of the tight junction. The pores at the top of the villi are the smallest, and the pores at the depressions are the largest. The integrity of tight junctions is calcium-dependent, and the removal of calcium can cause the rearrangement of tight junction proteins. At the adhesion junction, calcium removal may also destroy the integrity of the E-cadherin interaction. Some cytokines and growth factors can also weaken the barrier function of tight junctions.
The area immediately below the tight junctions is the adhesive zonules or adhesive junctions responsible for the adhesion between cells. The formation of tight junctions relies on the interaction between preformed cadherins in the adhesion junction area. Cell bypass includes tight junctions and connections between cells. The latter constitutes resistance to passage, which is opposed to osmosis and depends on the size and charge of the cell bypass. The resistance per unit area across the epithelium in the human intestine is different: the jejunum is 200/cm2, and the large intestine is 100/cm2. In the zonules, the actin-myosin I loop surrounds the epithelial cells and interferes with the solute penetration in this area. The last area of cell bypass is desmosomes, very close to the surface of the outer cell membrane of the basal layer of intestinal epithelial cells. The mediating filament connects desmosomes through insoluble thrombolysin. Desmosome core glycoprotein is the main desmo-cadherin. Desmoprotein is another kind of desmo-cadherin, its function is to connect insoluble plakins and mediation filament. The contribution of this area to cell bypass function is weaker than that of the other two areas located near the top.
Drugs with suitable physicochemical properties can pass through cells through passive diffusion. The physical and chemical properties of peptides or peptide mimics are not suitable, and it is difficult to cross cell membranes by transcellular pathways. Drug molecules entering human cells must pass through the lipid bilayer that constitutes the cell membrane. The bilayer is composed of four parts: 1. The outermost part contains a lot of water and interacts with other proteins and cell membranes; 2. The lower part contains polar heads. The molecular density in this region is very high and becomes the most difficult to diffuse area; 3. The third part contains a non-polar tail, which forms a permeation barrier based on the restriction of molecular size and shape; 4. The inner layer is the most hydrophobic and serves as a hydrophobic barrier. Osmotic resistance across cell pathways can be thought of as a series of resistances, where the apical cell membrane and the basolateral cell membrane are two resistances. They become a rate-limiting barrier when molecules are passively diffused. The cell membrane is only one of the barriers to the transcellular pathway. Drug molecules must also pass through the cytoplasm before leaving the basolateral cell membrane. There are various drug metabolizing enzymes in the cytoplasm that can metabolize drug molecules , Objectively reducing the drug transport through this pathway.
In addition to the physiological barrier, there is also a biochemical barrier in the gastrointestinal tract. The human body’s enzymes are located in the digestive tract lumen and intestinal epithelial cells, and there are microorganism-derived enzymes in the ileum and colon. The stomach is a mixture of hydrochloric acid and pepsin, and there are trypsin, chymotrypsin, pancreatic peptidase, and carboxypeptidase in the intestine. The proximal small intestine has a large surface area, many intestinal enzymes and transporters, and the strongest metabolic activity. It has been determined that there are phase I enzymes and phase II enzymes in the intestine, and the phase I enzymes belong to the CYP family. P450 enzymes are also present on the intestinal wall, the concentration is about 20 times lower than that of the liver, but the drug metabolism activity is close to that of the liver.
P-glycoprotein (PGP) is considered to be a multi-drug resistance-related protein (MRP), located in the top of the intestinal villi, in the brush-like border, throughout the small and large intestines. The concentration of PGP gradually increases from the stomach to the colon, the substrate range is very wide, and the affinity is different in different intestinal parts. PGP has the function of efflux pump, which returns the drug to the intestinal lumen, so that the metabolic enzyme acts on the drug again. The CYP enzyme and PGP coexist, strengthen the metabolism of the drug and reduce the drug absorption.