passive diffusion

Passive diffusion is the simplest way a drug crosses a cell membrane: it drifts from where it is concentrated to where it is dilute, with no energy spent and no helper proteins needed. Think of a drop of ink spreading through still water until it is evenly mixed — molecules naturally move 'downhill' from crowded to less-crowded regions.

Most drugs are absorbed this way. A cell membrane is essentially a fatty (lipid) sheet, so to slip through it a drug must dissolve in fat — that is, be lipophilic and uncharged. The driving force is the concentration gradient across the membrane: the greater the difference between the gut (or other site) and the blood, the faster the net movement. Because blood flow constantly carries absorbed drug away, the gradient is maintained and diffusion continues.

Passive diffusion has no upper speed limit set by a finite number of transporters, so it does not become 'saturated' the way carrier-mediated transport does — doubling the concentration roughly doubles the rate. It is also not selective and cannot move a drug against its gradient.

The catch is that only the uncharged, fat-soluble fraction of a drug diffuses well. Since many drugs are weak acids or bases that exist partly as charged ions, the local pH strongly influences how much is in the diffusible form — the idea captured by the pH partition hypothesis.