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Drug Absorption

Absorptio

For medical students2 min readUpdated 2026-10-10

Drug absorption (absorptio) is the process by which a drug overcomes biological barriers to enter the systemic circulation. The choice of administration route directly depends on the physicochemical properties of the molecule, primarily its water or lipid solubility.

Hydrophilic drugsEnter the bloodstream primarily via filtration through aqueous pores in the endothelium.

Lipophilic drugsEasily cross cell membranes by dissolving directly into the lipid bilayer.

TransportersATP-dependent proteins (e.g., P-glycoprotein) act as efflux pumps, reducing bioavailability.

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.

During parenteral administration routes, such as intramuscular or subcutaneous injections, the primary transport mechanism for hydrophilic drugs is filtration (filtratio).

Key features of filtration:

Pathway: Water-soluble molecules pass not through the cell membrane itself, but through specialized aqueous pores. These pores are cleft-like contacts located within the capillary endothelium.
Driving force: Filtration is a passive process driven by pressure gradients. The primary forces pushing molecules through these clefts are hydrostatic or osmotic pressures.

Transport of Lipophilic Compounds

Unlike hydrophilic drugs, fat-soluble (lipophilic) medicinal substances utilize a different mechanism to cross biological barriers.

Passive diffusion: This is the primary pathway for lipophilic molecules. Due to their high lipid affinity, they readily dissolve in the lipid bilayer of cell membranes and cross them freely.
Differences from hydrophilic molecules: It is crucial to understand that passive diffusion directly through the lipid layer of the membrane is unique to lipophilic compounds. Polar, ionized, and hydrophilic substances cannot cross this barrier in this manner and require aqueous pores or specialized carriers.

Biological Barriers and Protective Mechanisms

Although lipophilic drugs typically penetrate cell membranes easily, the body possesses robust systems that prevent their uncontrolled absorption and distribution. One such protective mechanism is the blood-brain barrier (BBB), which shields neural tissue.

The main factor preventing many drugs from entering 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 as efflux pumps.
Mechanism of action: They actively capture drug molecules that have already penetrated the cell and pump them back out into the intestinal lumen or systemic circulation.
Pharmacological consequences: The activity of these pumps is critical for pharmacokinetics because it directly decreases drug bioavailability and significantly reduces final concentrations in target tissues.

Mnemonic

H-H, L-L: Hydrophilic go through Hydro-pores (filtration), while Lipophilic dissolve in Lipids (diffusion).

Frequently asked questions

What mechanisms of drug penetration across membranes exist besides passive diffusion and filtration?

In addition to passive diffusion and filtration, drugs cross biological membranes via:

Active transport — carrier-mediated transport against a concentration gradient utilizing energy (e.g., for hydrophilic substances such as Levodopa).
Facilitated diffusion — carrier-mediated transport that occurs when a drug shares chemical similarity with endogenous substrates.
Pinocytosis — engulfment of large molecules (e.g., proteins) leading to intracellular vesicular transport to lysosomes.

How do the degree of ionization and environmental pH affect passive drug diffusion?

The degree of ionization and local pH determine a drug's ability to cross biological membranes. Only the non-ionized (lipophilic) fraction of a drug readily crosses the lipid bilayer. The ionization degree of weak acids and bases directly depends on pH. Altering gastric or intestinal acidity shifts the proportion of ionized molecules, which are absorbed more poorly. For example, increasing pH (alkalinization) slows the absorption of weakly acidic compounds, thereby diminishing their pharmacological effect.

What physiological factors influence the rate and completeness of drug absorption in the gastrointestinal tract?

Factors affecting gastrointestinal drug absorption include:

Presence of food — can mechanically block mucosal contact, delay gastric emptying, or alter gut wall blood flow.
GI motility — increased peristalsis shortens the contact time in the absorption window.
GI secretions — hydrochloric acid and digestive enzymes can degrade or inactivate compounds.
Metabolism — enterocyte enzymes (e.g., CYP3A4) metabolize drugs before they reach systemic circulation.
Active efflux — transport proteins (P-glycoprotein) pump molecules back into the intestinal lumen.

What is the first-pass effect (presystemic elimination)?

The first-pass effect is the extensive metabolism of a drug before it reaches systemic circulation. Following oral administration, drugs are absorbed and carried via the portal circulation to the liver, where they undergo biotransformation by microsomal enzymes. Consequently, a significant fraction of the drug may be inactivated (e.g., lidocaine is almost entirely cleared), greatly reducing bioavailability. In some cases, active metabolites are formed during first-pass metabolism (e.g., norethindrone).

What drives the absorption of hydrophilic substances during injections?

During intramuscular and subcutaneous administration, hydrophilic substances are absorbed via filtration. They pass through aqueous pores in the capillary endothelium driven by hydrostatic or osmotic pressure.

Why cannot hydrophilic substances penetrate via passive diffusion?

Passive diffusion requires molecules to pass directly through the lipid bilayer of the membrane. Hydrophilic (water-soluble) substances do not dissolve in lipids, thus requiring aqueous pores.

What role does P-glycoprotein play in drug absorption?

P-glycoprotein is an ATP-dependent transporter that acts as an efflux pump. It pumps drug molecules back into the blood or the intestinal lumen, thereby lowering bioavailability and drug concentration in tissues.

Go deeper

Structural features of aqueous pores and endothelial clefts in capillaries
Impact of hydrostatic and osmotic pressures on filtration rate
Structure and activation mechanisms of ATP-dependent transporters
Role of efflux pumps in forming the blood-brain barrier (BBB)
Concepts of bioavailability and tissue concentration in the context of P-glycoprotein function