Drug Absorption Mechanism: Passive Membrane Transport

The lipid-water partition coefficient directly determines the rate of drug diffusion across the cell membrane. Drugs with higher partition coefficients are more lipid-soluble and diffuse more rapidly through the membrane. This property is fundamental to passive transport, as only lipid-soluble drugs can traverse the lipid bilayer efficiently down the concentration gradient.

Ionized drug forms are lipid-insoluble and cannot permeate the cell membrane. Only nonionized, lipid-soluble forms can diffuse readily across the lipid bilayer. Since the ionized species lacks the chemical properties necessary to dissolve in lipids, it remains trapped on one side of the membrane regardless of concentration differences.

The drug's pKa and the pH gradient across the membrane determine whether a drug exists in ionized or nonionized form at different locations. When the drug's pKa is higher than the local pH, the drug remains primarily undissociated and can diffuse across the barrier. When pKa is lower than the pH, the drug readily dissociates into its ionized form, which cannot cross the membrane.

In the stomach's acidic environment, a weakly acidic drug remains primarily undissociated because the gastric pH is lower than the drug's pKa. This nonionized form is lipid-soluble and diffuses easily across the stomach barrier. Once in the plasma, where pH is higher than the drug's pKa, the drug dissociates into its ionized form, which cannot diffuse back through the membrane.

After a weakly acidic drug crosses the stomach membrane into plasma, the higher pH causes the drug to dissociate into its ionized form. Because the ionized form cannot diffuse through the membrane, it becomes trapped in the plasma compartment. This creates a concentration gradient that favors continued drug movement from the stomach into plasma while preventing backflow.

A drug must be small and lipid-soluble to be absorbed via passive transport. The drug's ability to dissolve in lipids, measured by its lipid-water partition coefficient, determines diffusion rate. Additionally, the drug must exist in a nonionized form at the absorption site to cross the lipid bilayer, which depends on the drug's pKa relative to the local pH.

Passive transport relies on the drug's inherent lipid solubility and concentration gradient to move across membranes without cellular energy. Unlike carrier-mediated membrane transport, passive transport does not require specific transport proteins or ATP. This mechanism is limited to small, lipid-soluble drugs and is driven entirely by physicochemical properties like the lipid-water partition coefficient and pH-dependent ionization.