Mechanisms of hydrophilic drug absorption
For water-soluble (hydrophilic) compounds, crossing biological membranes presents a specific challenge because they cannot freely dissolve in the fats of cell walls.
With parenteral routes of administration, such as intramuscular or subcutaneous injections, filtration (filtratio) becomes the primary transport mechanism for hydrophilic drugs.
Features of the filtration process:
- Pathway: Water-soluble molecules pass not through the cell membrane itself, but through specialized aqueous pores. These pores are cleft-like junctions located in the capillary endothelium.
- Driving force: Filtration is not an active process; it occurs under the influence of a pressure gradient. The main factors driving molecules through the cleft junctions are hydrostatic or osmotic pressure.
Transport of lipophilic compounds
Unlike hydrophilic drugs, fat-soluble (lipophilic) medicinal substances have a different mechanism for crossing biological barriers.
- Passive diffusion: This is the main pathway for lipophilic molecules. Due to their affinity for fats, they can freely dissolve in the lipid bilayer of cell membranes and pass through them.
- Differences from hydrophilic molecules: It is important to understand that passive diffusion directly through the lipid layer of the membrane is characteristic exclusively of lipophilic compounds. Polar, ionized, and hydrophilic substances cannot cross this barrier in this manner and require pores or specialized carriers.
Biological barriers and protective mechanisms
Although lipophilic drugs generally cross cell membranes easily, the body possesses powerful systems that prevent their uncontrolled absorption and distribution. One such protective mechanism is the blood-brain barrier (BBB), which protects brain tissue.
The main factor preventing many drugs from penetrating protected tissues is ATP-dependent transporters. A classic example of such a transporter is P-glycoprotein.
How these barriers work:
- Efflux pumps: ATP-dependent transporters function on the principle of "efflux pumps" (from English efflux pumps).
- Mechanism of action: They actively capture drug molecules that have already managed to enter the cell and pump them back out into the intestinal lumen or systemic circulation.
- Pharmacological consequences: The action of these pumps is critical for pharmacokinetics because it directly leads to decreased drug bioavailability and significantly reduces its final concentration in target tissues.
Briefly: answers to topical questions
What mechanisms of drug penetration through membranes exist besides passive diffusion and filtration?
In addition to passive diffusion and filtration, drugs penetrate biological membranes through the following mechanisms:
- Active transport — the transport of substances against a concentration gradient, requiring energy expenditure and the participation of transport proteins (e.g., for hydrophilic substances such as Levodopa).
- Facilitated diffusion — transport involving carriers, possible if the drug shares chemical similarity with endogenous substrates.
- Pinocytosis — a method of engulfing large molecules (e.g., proteins) with their subsequent delivery to intracellular lysosomes.
How do the degree of ionization and medium pH affect passive diffusion of drugs?
The degree of ionization and the pH of the medium determine the ability of a drug to cross biological membranes. Only the non-ionized (lipophilic) fraction of the drug easily passes through the lipid bilayer. The degree of ionization of weak acids and bases directly depends on the pH level. Changes in the acidity of the stomach or intestines alter the proportion of ionized molecules, which are absorbed more poorly. For instance, an increase in pH (alkalinization of the medium) slows down the absorption of weakly acidic compounds, thereby diminishing their pharmacological effect.
What physiological factors influence the completeness and rate of drug absorption in the gastrointestinal tract?
The completeness and rate of drug absorption in the gastrointestinal tract are influenced by a number of physiological factors:
- Presence of food — can create a physical barrier to contact with the mucosa, delay gastric emptying, or stimulate blood flow in the intestinal wall.
- GI motility — increased peristalsis reduces the residence time of the drug in the absorption zone.
- GI secretions — hydrochloric acid and digestive enzymes can degrade or inactivate substances.
- Metabolism — enterocyte enzymes (such as CYP3A4) transform substances even before they reach the bloodstream.
- Active efflux — transport proteins (P-glycoprotein) pump molecules back into the intestinal lumen.
What is the first-pass effect in the liver (presystemic elimination)?
The first-pass effect in the liver involves the intensive metabolism of drugs before they reach the systemic circulation. When administered orally, drugs are absorbed and pass via the portal circulation to the liver, where they are exposed to microsomal enzymes. As a result, a significant portion of the substance may be inactivated (e.g., lidocaine is broken down almost entirely), leading to a marked decrease in bioavailability. In some cases, active metabolites can be formed during the first pass (e.g., norethisterone).
H-H, L-L: Hydrophilic substances go through Hydro-pores (filtration), while Lipophilic ones dissolve in Lipids (diffusion).
Class and exam questions
How does the absorption of hydrophilic substances occur during injections?
During intramuscular and subcutaneous administration, hydrophilic substances are absorbed via filtration. They pass through aqueous pores in the capillary endothelium under the action of hydrostatic or osmotic pressure.
Why cannot hydrophilic substances penetrate via passive diffusion?
Passive diffusion implies the passage of a molecule directly through the lipid bilayer of the membrane. Hydrophilic (water-soluble) substances do not dissolve in lipids, which is why they require aqueous pores.
What role does P-glycoprotein play in drug absorption?
P-glycoprotein is an ATP-dependent transporter that functions as an efflux pump. It pumps drug molecules back into the blood or intestinal lumen, thereby reducing bioavailability and tissue drug concentration.
What else to study on this topic
- Structural features of aqueous pores and cleft junctions in capillary endothelium
- Influence of hydrostatic and osmotic pressure on filtration rate
- Structure and activation mechanism of ATP-dependent transporters
- The role of efflux pumps in forming the blood-brain barrier (BBB)
- The concepts of bioavailability and tissue concentration in the context of P-glycoprotein function
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