Main Pathways of Passive Diffusion
The process of diffusio passiva occurs in the body via two independent pathways, each imposing specific requirements on the chemical and physical properties of molecules.
- Transcellular diffusion (via the lipid bilayer). The molecule dissolves directly in the lipid matrix of the cell membrane and passes through it. To successfully cross this barrier, the substance must possess high lipophilicity (a strong affinity for fats) and lack an electrical charge, meaning it must be in a non-ionized form. This is the primary pathway for most pharmacological agents.
- Paracellular diffusion (via aqueous pores and channels). In this scenario, the substance bypasses lipids by moving through intercellular clefts or specialized aqueous channels. This path is open exclusively to hydrophilic compounds with very small molecular sizes—their diameter must be smaller than the pore itself. Classic examples of substances using this pathway include water, ions, and small water-soluble molecules such as urea (urea).
Role of Lipophilicity and Amphiphilicity
The rate at which a substance penetrates the membrane lipid bilayer directly depends on its lipophilicity. In pharmacology, the universal measure of this property is the partition coefficient in the standardized system 'organic solvent (octanol) — water'. The higher this value, the easier the molecule integrates into the lipid structure of the cell wall, whereas a low coefficient indicates hindered penetration.
However, a major problem arises with absolute lipophilicity. If a molecule has an excessive affinity for fats, it may simply become 'trapped' inside the lipid phase of the membrane, losing the ability to enter the aqueous environment of the intracellular fluid (cytosolum) or extracellular space.
Consequently, to successfully exit the membrane, a molecule must possess amphiphilicity—a delicate balance between lipophilicity and water solubility. Chemically, this ability is ensured by electronegative atoms (oxygen, nitrogen, or sulfur) within the substance's structure. They interact with water molecules, forming hydrogen bonds and guaranteeing the necessary degree of hydrophilicity.
Fick's Law and Rate Factors
The kinetics of passive diffusion are mathematically and conceptually described by Fick's law. The rate of the process ($dQ/dt$) is calculated by multiplying the concentration difference by the surface area and the diffusion coefficient, and then dividing the result by the membrane thickness.
The key factors influencing the rate of diffusional transport include:
- Concentration gradient ($C_1 - C_2$): acts as the primary driving force of the process.
- Surface area: exhibits direct proportionality (the larger the available area, the faster the diffusion).
- Diffusion coefficient: a parameter determined predominantly by the lipophilicity of a given substance (the octanol-water coefficient).
- Membrane thickness: characterized by inverse proportionality (barrier thickening naturally slows down the process).
- Molecular weight: the rate of transport is inversely proportional to the square root of the molecular mass, meaning larger structures move significantly slower.
- Additional parameters: spatial molecular conformation and ambient temperature also influence process intensity.
Limitations for Charged Molecules and Filtration
The lipid bilayer is a formidable barrier to charged particles and polar compounds. Ions cannot freely cross the membrane for two reasons. First, they are counteracted by the cell membrane potential. Second, the hydration phenomenon applies: in an aqueous environment, charged particles are immediately surrounded by a dense shell of water molecules, physically preventing their close contact with lipids. Polar hydrophilic substances also barely penetrate the bilayer due to extremely low fat solubility.
An alternative route for them is filtration—passive diffusion in an aqueous medium via aqueous pores (aquaporinae) formed by membrane glycoproteins.
However, this pathway has strict anatomical limitations. The diameter of aqueous pores ranges between 0.3–0.4 nm, making them permeable only to water and small molecules (e.g., glycerin — glycerinum). Meanwhile, the vast majority of hydrophilic drug substances have molecular diameters exceeding 1 nm. The main pharmacokinetic conclusion is that hydrophilic drugs physically cannot pass through pores or enter cells via simple filtration, making this pathway insignificant for most medications.