Talking about: Factors and Absorption Routes Affecting Oral Drug Absorption

Oral administration is the most common route of administration and is considered one of the most convenient
.
However, the poor solubility and dissolution rate of the drug, the absorption barrier, the metabolism into the blood system and the excretion will all become obstacles to oral administration
.
Some drugs can overcome the above barriers to enter the human circulation and reach target organs smoothly, so they have high bioavailability; while other drugs, such as central nervous system (CNS) drugs and drug-resistant anti-tumor drugs, are difficult to achieve.
reach target organs because they have to cross other physiological barriers (such as the blood-brain barrier) in addition to the above-mentioned barriers
.
Therefore, in order to better enable oral drugs to reach target organs and exert their efficacy, in-depth research and overcoming these absorption barriers are required
.
Intestinal Absorption Barrier The intestinal tract is the main absorption site of drugs, but its absorption is selective and affected by many factors
.
The first is the molecular weight of the compound
.
Macromolecular substances are generally not absorbed unless administered in very small doses, as in the case of antigens such as polio vaccine
.
In addition, a variety of enzymes in the liver and intestine can degrade macromolecules such as proteins, polypeptides, and polysaccharides into small molecules.
The small molecules formed after degradation are often hydrophilic and can only enter cells under the mediation of transporters
.
This molecular weight restriction is caused by the mechanical barrier formed by enterocytes, which prevent the passage of drugs through the membranes of enterocytes, the intestinal mucosa, and the tight junctions between enterocytes
.
Liver Absorption Barrier The difference between the liver barrier and the intestinal barrier is that it is more uniform.
The liver barrier is mainly composed of a large number of drug metabolizing enzymes present in the liver, which can inactivate the drugs that are absorbed through the intestine but not metabolized by the intestinal enzymes
.
Both phase I and phase II metabolic enzymes are expressed in the liver, with a wide variety and abundant content
.
Among them, the phase I enzyme system is mainly the cytochrome P450 mixed multifunctional oxidase superfamily
.
The metabolites formed by these enzymes can be further combined with hydrophilic groups by phase II metabolizing enzymes, so the final metabolites formed are highly hydrophilic, and can enter the kidneys through bile or plasma, and finally be excreted in the urine. .
Another important barrier of the liver is various efflux transporters distributed on the bile canalicular membrane
.
These transporters excrete the parent compound, phase I metabolites, and phase II metabolites from the liver into bile and then re-enter the gut
.
That is to say, the drug must be dissolved and released from the drug when it passes through the gastrointestinal tract with absorption ability, so that it can be absorbed and utilized.
Let's take a look at what is drug absorption and what are the absorption routes? Absorption is the process by which a drug enters the blood or lymph through the gastrointestinal tract
.
Generally speaking, there is no special difference in the absorption of drugs and food, but the absorption mechanisms of the two are different, and the absorption sites in the gastrointestinal tract and the absorption conditions of different parts are also different
.
Drug absorption depends on both physicochemical and biological factors, the former including formulation (such as the disintegration rate and release rate of the drug from the polymer matrix) and the drug itself (such as solubility and lipophilicity), biological factors such as gastric emptying rate and Intestinal transit time,
etc.
*A-passive diffusion across cells; B-carrier-mediated diffusion across cells; C-paracellular diffusion; D-transcellular diffusion via endocytosis; E-transcellular diffusion by fusion with cell membrane lipid particles; F- Paracellular diffusion involving tight junction regulators; G-transcellular diffusion regulated by polarized efflux The process by which pores are absorbed into the systemic circulation
.
Intestinal epithelial cells are connected to each other by tight junctions at the top of the cells, and the degree of tight junctions varies widely in different parts of the body
.
The intercellular space is only 0.
01% of the total surface area of ​​intestinal epithelial cells
.
In general, absorbing epithelial cells, such as intestinal epithelial cells, have larger intercellular spaces and therefore more leakage of compounds
.
The lower the gastrointestinal tract, the weaker the role of the alternative cell pathway, as the spaces between the epithelial cells become smaller and the number decreases
.
Passive Diffusion Passive diffusion is the main route of absorption for low molecular weight lipophilic drugs
.
During the absorption process, drug molecules pass through the lipid membrane from the gastrointestinal tract in the high concentration area by passive diffusion and enter the blood in the low concentration area
.
Blood flow enables the dissolved drug to be continuously taken away by the blood circulation after passing through the membrane, so that the drug in the local blood flow is always kept at a low concentration level
.
Carrier-mediated transport Theoretically, lipophilic drugs can easily pass through cells
.
Lipid cell membranes are not diffusion and absorption barriers for small molecule lipophilic drugs
.
In the gut, drugs and other molecules can cross the intestinal epithelium by diffusion or carrier-mediated mechanisms
.
There are many specific carrier-mediated transport systems in the body, especially in the intestinal tract, which play an important role in absorbing the ions and nutrients needed by the body
.
Carrier-mediated transport exists in two forms: active carrier-mediated transport and passive carrier-mediated transport; active carrier-mediated transport occurs through dual-function carriers coupled to Na+ or H+
.
This process requires energy and proceeds through a reversible concentration gradient; in contrast, passive carrier media do not require energy and can only follow the concentration gradient
.
Active transport Unlike passive diffusion, active transport requires transport proteins on the apical membrane of columnar uptake cells
.
Active transport is carried out against the concentration gradient, that is, transporting from a low concentration area to a high concentration area, which is an energy-consuming process
.
The energy required comes from the hydrolysis of ATP.
The hydrolysis may be directly generated by the interaction between the drug and the transporter, or indirectly from the transmembrane Na+ concentration gradient and/or the potential difference between the two sides of the membrane generated by normal cellular energy metabolism
.
Since active transport requires energy from cellular metabolism, the entire process is temperature-dependent
.
Characteristics of active transport: • Requires one or more carrier proteins • Requires energy generated by ATP hydrolysis • Temperature-dependent • Competitive inhibition of facilitated diffusion by similar substrates or specific inhibitors The difference is that it cannot be done against the concentration gradient
.
Facilitated diffusion does not need to consume energy and is driven by concentration gradients, which is the same as passive diffusion
.
When the size and polarity of the drug molecules are suitable, the rate of facilitated diffusion along the concentration difference may be faster than expected
.
Like active transport, the facilitated diffusion process is saturated and inhibited by competitive inhibitors
.
In the process of drug absorption, with the exception of nucleoside drugs, facilitated diffusion has little effect on the absorption of other drugs
.
The absorption of oral drugs is the key to improve the bioavailability of oral drugs
.
Therefore, before designing an oral drug delivery system, the biopharmaceutical properties of the drug should be fully grasped, especially the effects of the membrane permeability and first-pass effect of the drug on the transmembrane transport and pre-system metabolism of the drug, and the gastric Physiological barrier of the gut
.
Therefore, according to the different characteristics of the drug, according to the main barriers and factors that limit its absorption, choosing a reasonable absorption-promoting method so that the drug can exert its curative effect more efficiently and with less toxicity still needs the continuous practice and exploration of pharmacists
.