Cell membranes and transport mechanisms
The structural basis of any cellular barrier is the phospholipid bilayer. Its organization is strictly ordered: the hydrophilic heads of the molecules face outward (toward aqueous media), while the hydrophobic tails are hidden inside the membrane. It is this hydrophobic core that creates a reliable barrier for polar compounds.
The movement of drugs and other substances across membranes occurs via two main pathways:
- Passive transport: the movement of substances along a concentration gradient. This process does not require energy expenditure. Lipophilic molecules most often move in this way via passive diffusion (diffusio passiva).
- Active transport: the movement of substances against a concentration gradient or with the mandatory participation of specific carriers. This process is always accompanied by energy expenditure.
Epithelial and endothelial barriers
Tissue barriers play a crucial role in the distribution of substances throughout the body.
The epithelial barrier serves as a significant obstacle to hydrophilic compounds. For example, due to this barrier, such substances show poor absorption from the lung surface and lack reabsorption in the renal tubules. Lipophilic compounds usually cross the epithelium freely, but the body employs a protective mechanism of efflux: specialized membrane transporter proteins (such as P-glycoprotein) are capable of capturing molecules that have entered the cell and actively pumping them back out (e.g., from an enterocyte back into the intestinal lumen).
The endothelial barrier (capillary wall) varies depending on the tissue:
- General-type capillaries (skeletal muscles, subcutaneous tissue, internal organs). There are large intercellular gaps (fenestrae) measuring about 2 nm or more between endothelial cells (cellulae endotheliales). Hydrophilic substances easily penetrate into tissues via filtration through these clefts, ensuring rapid exchange between blood and tissue fluid.
- Capillaries of the brain (CNS). Fenestrae are completely absent, and cells are tightly apposed. The transport of hydrophilic substances is impossible.
Histohematic barriers
Histohematic barriers are specialized partitioning structures between the blood and tissue fluid of specific organs. Their main function is to protect the vulnerable internal environment from toxins and xenobiotics circulating in the bloodstream.
The main types include:
- Blood-brain barrier (BBB) (barriera haematoencephalica). Protects the brain. Due to endothelial tight junctions, water-soluble polar xenobiotics literally "bounce off" the capillary wall. Only lipophilic substances can penetrate via passive diffusion.
- Blood-ocular barrier. Isolates the ocular media and is impermeable to hydrophilic polar drugs.
- Placental barrier. Protects the developing fetus.
- Reproductive barriers: blood-testis barrier (between the blood and the contents of the seminiferous tubules) and blood-follicular / blood-ovarian barrier (protection of the ovaries). Since lipophilic substances can easily diffuse into these tissues, protection is provided by ATP-dependent transport proteins. For example, cyclosporine (Cyclosporinum), a lipophilic drug toxic to spermatogenesis, is actively eliminated by P-glycoprotein, minimizing its damaging effect.
Briefly: answers to topical questions
What mechanisms of drug transport across cell membranes are distinguished in pharmacology?
Pharmacology distinguishes several main mechanisms of drug transport across cell membranes. These include:
- Passive transport — movement of substances along a concentration gradient without energy expenditure (includes passive diffusion, diffusio passiva).
- Active transport — movement against a concentration gradient or with the participation of carriers, requiring energy expenditure (ATP).
- Facilitated diffusion — transport involving specific systems for substances with a chemical similarity to endogenous substrates.
- Pinocytosis and receptor-mediated endocytosis — cellular uptake of fluid or specific macromolecules.
What types of histohematic barriers exist in the human body?
Specialized histohematic barriers exist in the human body to protect the internal environment of organs from xenobiotics. The following types of barriers are distinguished:
- Blood-brain barrier (barriera haematoencephalica) — protects the brain and maintains CNS homeostasis.
- Blood-ocular barrier — protects the ocular media and is impermeable to hydrophilic polar substances.
- Blood-testis barrier — located between the blood and the contents of the seminiferous tubules.
- Blood-follicular barrier (blood-ovarian) — protects the ovaries.
- Blood-placental barrier (placental) — separates the maternal and fetal bloodstreams, functioning as a selective transport system.
Which cellular and tissue structures form the blood-brain barrier?
The blood-brain barrier is formed by three levels of cellular and tissue structures. It comprises:
- Brain capillary endothelial cells — form a double-membrane layer, lack intercellular clefts, and are connected by tight junctions that block paracellular transport.
- Basement membrane — contains fibrillar components and specific cells.
- Pericytes (pericytae) — located within the basement membrane.
- Astrocytes (astrocyti) — glial cells whose processes form the astrocytic endfeet (glial limiting membrane) covering 85–90% of the capillary surface.
Which transporter proteins provide active efflux of xenobiotics from cells?
Specialized membrane transporter proteins provide the active efflux (pumping out) of xenobiotics and drugs from cells. The main efflux systems include:
- P-glycoprotein (P-glycoproteinum / MDR1) — a key protein functioning as a membrane "pump" and ensuring the active removal of substances from the cell.
- ABC transporters (ATP-binding cassette) — a family of ATP-dependent cassette proteins that provide active substance elimination with energy expenditure.
- MRP1 and BCRP — alternative efflux systems also associated with cellular drug resistance.
What physicochemical properties of drugs determine their ability to cross the placental barrier?
The ability of drugs to cross the placental barrier (trophoblast membrane, trophoblastus) is determined by their lipophilicity, size, and degree of ionization. The following key physicochemical properties are distinguished:
- Lipophilicity — lipophilic compounds readily cross via passive diffusion, whereas hydrophilic ones require transporter proteins.
- Molecular weight (MW) — substances with MW ≤ 500 Daltons diffuse easily, those from 500 to 1000 Da penetrate at a low rate, and those > 1000 Da practically do not cross the barrier.
- Degree of ionization — depends on the pH gradient; weak bases are ionized in the more acidic fetal plasma, lose lipophilicity, and accumulate (ion-trapping phenomenon).
What methods exist for artificially overcoming the blood-brain barrier for targeted drug delivery?
Pharmacological and technological strategies are used to artificially overcome the blood-brain barrier for targeted drug delivery to the central nervous system. The main methods include:
- Use of prodrugs (Prodrugs) — administration of an inactive compound that binds to specific membrane carriers or undergoes structural modification (increased lipophilicity) to cross the membrane, and is subsequently activated in brain tissue.
- Inhibition of efflux transporters — combining the target drug with a P-glycoprotein inhibitor (e.g., verapamil), which prevents the drug from being pumped back out of the brain into the blood.
- Nanotechnology — the use of biodegradable nanoparticles (10–1000 nm in size) in which the drug substance is encapsulated inside, covalently bound, or sorbed on the surface.
To easily remember capillary permeability, imagine a sieve: in muscles, it is a coarse sieve (with 2 nm pores) that lets "water" through (hydrophilic substances via filtration). Whereas in the brain (the BBB), it is a monolithic wall of tight junctions through which only "fat" can imperceptibly "seep" (lipophilic substances via diffusion).
Class and exam questions
Why do hydrophilic polar substances not penetrate the brain?
In the brain capillaries, endothelial cells are tightly apposed without forming intercellular clefts. Since hydrophilic molecules cannot dissolve in the lipid membrane and there are no pathways for their filtration, they cannot cross the blood-brain barrier.
How do lipophilic substances cross cellular barriers?
Lipophilic compounds move across the phospholipid bilayer of cells via passive diffusion (diffusio passiva). This mechanism operates in all types of capillaries and cell membranes because it requires neither energy expenditure nor the presence of pores.
How does the blood-testis barrier protect tissues from lipophilic toxins?
Since lipophilic substances can freely enter tissues via passive diffusion, protection is provided by the efflux mechanism. ATP-dependent proteins (such as P-glycoprotein) recognize foreign molecules (like cyclosporine) and actively pump them back into the blood.
What else to study on this topic
- Structure and properties of the phospholipid bilayer
- Classification of transport: passive and active mechanisms
- Efflux mechanism and clinical significance of P-glycoprotein
- Anatomy of the blood-brain barrier (tight junctions)
- Placental barrier functions in fetal protection
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