Passive diffusion is a critical process that allows small lipophilic drugs to cross the cell membrane along a concentration gradient. This mechanism's efficiency depends on four primary factors: the membrane's surface area, the drug's lipid-water partition coefficient, the concentration gradient, and the membrane's thickness.

When administered orally, drugs establish a substantial concentration gradient between the gastrointestinal (GI) lumen and the bloodstream, expediting their diffusion into the circulatory system. Drugs with high lipid solubility, denoted by an elevated partition coefficient, diffuse readily across membranes.

The small intestines play a pivotal role in this process, with duodenal microvilli increasing the surface area, which enhances the rate of drug absorption. Conversely, the diffusion of drugs into the brain is severely restricted by the thick, glial cell-lined blood-brain barrier.

Many drugs are weak acids or bases that can exist in nonionized and ionized forms, depending on the surrounding environment. The nonionized form is lipid-soluble and easily diffusible across a membrane, while the ionized form is relatively lipid-insoluble and poorly diffusible across a membrane. Alterations in the pH levels of bodily fluids influence the diffusion of such weak acids or bases. Overall, passive diffusion is a complex interplay of various factors that govern the rate at which drugs are absorbed in the body.