When a drug is administered orally (peroral route), it must traverse several barriers in the gastrointestinal tract before reaching systemic circulation.
The main mechanisms include:
1) Passive Diffusion
Passive diffusion is the most common mechanism by which drugs are absorbed. It occurs in two ways:
A) Transcellular Passive Diffusion
Definition: Movement of drug molecules from a region of higher concentration (inside the GI lumen) to a region of lower concentration (blood) across the cell membrane.
Driving Force: Concentration gradient.
Characteristics:
Does not require energy or specialized carrier proteins.
Most drugs are absorbed via passive diffusion.
Governed by Fick’s first law (flux proportional to the concentration gradient).
Lipophilicity, molecular size, and degree of ionization play crucial roles.
B) Paracellular Passive Diffusion
Definition: Movement of drug molecules through the spaces (tight junctions) between cells, rather than through the cells themselves.
Limitations:
Tight junctions in the intestinal epithelium restrict movement of large or highly charged molecules.
Less significant than transcellular diffusion due to the limited space between cells.
Fick’s Law of Diffusion
Describes drug diffusion across biological membranes:
Where:
J = Diffusion rate
D = Diffusion coefficient
ΔC = Concentration gradient
Δx = Membrane thickness
The rate of diffusion is influenced by lipid solubility, membrane thickness, surface area, drug concentration, and environmental pH.
2) Facilitated Diffusion
Definition: A carrier-mediated process that does not require energy (ATP); instead, it uses transport proteins (e.g., GLUT transporters for glucose).
Driving Force: Concentration gradient.
Characteristics:
Requires a specific transport protein.
Can become saturated if all carrier proteins are occupied.
Specific for certain structural types of drugs.
3) Active Transport
Definition: Transport that requires energy (ATP) and carrier proteins to move drugs against their concentration gradient (from lower to higher concentration).
Characteristics:
Highly selective for specific drugs or nutrients.
Can be saturated at higher concentrations of substrate.
Subject to competition from substances using the same carrier.
4) Endocytosis (Pinocytosis/Phagocytosis)
Definition: A process by which cells engulf fluid or solid particles.
Types:
Pinocytosis: "Cell drinking"; involves uptake of liquids or very small particles.
Phagocytosis: "Cell eating"; involves uptake of larger particles (not very common for most drug absorption).
Relevance: Mostly important for large macromolecules such as proteins, peptides, or complex lipid structures.
5) Solvent Drag (Bulk Flow Transport)
The movement of water across membranes carries dissolved drugs along with it.
Occurs in processes like osmosis and bulk flow.
Plays a role in drug absorption in the intestine and kidney.
6) Ion-Pair Transport
Involves ionized drugs forming complexes with counter-ions, facilitating transport across membranes.
Important for drugs that are poorly absorbed via passive diffusion.
Affected by pH, drug concentration, and the presence of competing ions or transporters.
