Exploring Pharmacology: Which of these are ways substances can cross the blood-brain barrier?

October 12, 2025 •

3 min read

Over 98% of small-molecule drugs are unable to cross the blood-brain barrier (BBB), presenting a major challenge for treating central nervous system (CNS) disorders. Understanding which of these are ways substances can cross the blood-brain barrier? is crucial for developing targeted therapies and navigating this protective physiological filter.

Quick Summary

The blood-brain barrier is a highly selective filter. Substances cross through various pathways, including passive diffusion for lipid-soluble molecules, carrier-mediated transport for nutrients, and transcytosis for larger compounds like proteins. Efflux pumps also actively remove unwanted substances.

Key Points

Passive Diffusion: Small, lipid-soluble molecules like ethanol and nicotine freely cross the BBB by passing directly through the cell membrane, driven by a concentration gradient.
Carrier-Mediated Transport: Nutrients vital for brain function, such as glucose and amino acids, are actively transported across the BBB by specific protein carriers like GLUT-1 and LAT1.
Receptor-Mediated Transcytosis: Large proteins and antibodies can be delivered across the BBB by binding to specific receptors on the endothelial cells, which then trigger vesicle formation and cellular transport.
Adsorptive-Mediated Transcytosis: Positively charged molecules are transported via endocytosis after a nonspecific electrostatic attraction to the negatively charged cell surface.
Efflux Pumps: The BBB contains active transporters, such as P-glycoprotein, that pump many drugs and unwanted substances out of the brain and back into the bloodstream.
Strategic Drug Design: For many CNS drugs, pharmacologists must chemically modify substances or package them in nanoparticles to effectively use or bypass the natural BBB transport mechanisms.

The blood-brain barrier (BBB) is a dynamic and highly selective barrier of capillaries that regulates the passage of substances from the blood into the brain's extracellular fluid. This barrier, formed by specialized endothelial cells with tight junctions, protects the central nervous system (CNS) from harmful agents. However, this protection also complicates drug delivery to the brain.

The Primary Mechanisms of Blood-Brain Barrier Transport

Substances can cross the BBB through several main mechanisms:

Passive Transcellular Diffusion

Small, lipid-soluble molecules can cross the BBB by dissolving in and diffusing through the lipid bilayer of the endothelial cells, moving down their concentration gradient. This process is non-saturable and depends on the molecule's properties like lipid solubility and molecular weight. Examples include psychoactive drugs like ethanol, nicotine, and diazepam, as well as some anesthetics and barbiturates. However, excessive lipid solubility can trap substances in the cell membranes.

Carrier-Mediated Transport (CMT)

This facilitated diffusion process is used for polar molecules that cannot freely cross the lipid membrane. Specific protein carriers in the endothelial cell membranes bind to these substances and transport them across. This is essential for transporting vital nutrients like glucose and amino acids into the brain. Glucose, for example, uses the GLUT-1 carrier, while L-DOPA uses the LAT1 carrier. Drug designers can exploit this by creating drugs that mimic these endogenous substances.

Receptor-Mediated Transcytosis (RMT)

RMT is a mechanism for transporting larger molecules such as proteins and antibodies. It involves specific receptors on endothelial cells that bind to the molecule, triggering endocytosis. The resulting vesicle is then transported across the cell and releases its contents via transcytosis. Endogenous proteins like insulin and transferrin use RMT, and monoclonal antibodies can be engineered to utilize this pathway.

Adsorptive-Mediated Transcytosis (AMT)

This less specific mechanism relies on the electrostatic attraction between positively charged molecules and the negatively charged surface of endothelial cell membranes. This attraction induces endocytosis and subsequent transcytosis. AMT can be used for drug delivery by attaching therapeutic agents to cationic peptides.

Efflux Pumps

Efflux pumps, such as P-glycoprotein (P-gp), are active transporters that work against the above mechanisms by pumping many substances, including drugs, out of the brain and back into the blood. These pumps are a crucial part of the BBB's protective function, and inhibiting them is a potential strategy to increase drug concentration in the brain.

Comparison of Blood-Brain Barrier Transport Mechanisms


Mechanism	Molecule Type	Specificity	Energy Required	Key Features
Passive Transcellular Diffusion	Small, lipid-soluble	Low	No	Directly passes through cell membrane; relies on concentration gradient.
Carrier-Mediated Transport (CMT)	Nutrients, small polar molecules	High	No (Facilitated Diffusion)	Uses specific protein carriers (e.g., GLUT-1, LAT1).
Receptor-Mediated Transcytosis (RMT)	Large proteins, antibodies	High	Yes (Endocytosis)	Requires specific receptor binding to trigger vesicle formation.
Adsorptive-Mediated Transcytosis (AMT)	Positively charged substances	Low	Yes (Endocytosis)	Relies on nonspecific electrostatic attraction to the cell surface.
Efflux Pumps (e.g., P-gp)	Various, often lipophilic drugs	Medium	Yes (Active Transport)	Actively expels substances from the brain back into the blood.

Novel Strategies for Enhanced Drug Delivery

Overcoming the BBB for drug delivery, especially for complex molecules, has led to innovative approaches:

Nanoparticle-based technologies: Nanoscale platforms can deliver drugs and utilize surface modifications for transcytosis or efflux inhibition.
Intranasal delivery: This method allows drugs to bypass the BBB through neuronal pathways to reach the CNS quickly.
Focused Ultrasound (FUS): When combined with microbubbles, FUS can temporarily disrupt the BBB, allowing drug passage.

Conclusion

Navigating the blood-brain barrier is a primary challenge in delivering therapies for neurological conditions. The choice of drug delivery method depends on the substance's characteristics, utilizing pathways like passive diffusion for small lipid-soluble molecules or receptor-mediated transcytosis for larger biologics. A deeper understanding of these transport mechanisms is crucial for developing effective treatments for brain diseases. For further reading, consult resources such as Basic Neurochemistry from the NIH National Center for Biotechnology Information at ncbi.nlm.nih.gov/books/NBK28180/.

Frequently Asked Questions

Molecules that can cross via passive diffusion are typically small, non-polar, and lipid-soluble. Examples include ethanol, nicotine, and many psychoactive drugs.

Essential nutrients are transported via carrier-mediated transport. Specialized protein carriers, such as the GLUT-1 transporter for glucose, facilitate their entry across the barrier.

The tight junctions and efficient efflux pumps of the BBB prevent most drugs, especially larger molecules, from entering the brain. This requires complex strategies to either modify drugs or use specialized delivery systems to overcome the barrier.

The 'Trojan horse' approach uses endogenous ligands or monoclonal antibodies that bind to specific receptors on the BBB. This binding triggers receptor-mediated transcytosis, ferrying the attached drug into the brain.

No, many factors influence the rate of BBB penetration, including molecular weight, charge, and lipid solubility. Furthermore, efflux pumps can actively remove substances, even if they initially cross.

New technologies include focused ultrasound combined with microbubbles to transiently and locally open the barrier, as well as the use of nanoparticle-based delivery systems and intranasal administration.

Efflux pumps, such as P-glycoprotein, can limit the rate and extent of drug uptake by actively pumping them out of the brain, potentially leading to lower-than-intended drug concentrations at the target site.