ion trapping

Imagine a turnstile that only lets people through if they take off a bulky backpack. A drug molecule can only cross a membrane when it is uncharged; the charged form is the backpack that won't fit. If a molecule loses its charge to cross into a compartment and then picks the charge back up once inside, it cannot get back out, so it accumulates. That is ion trapping.

The effect arises because the two sides of a membrane often have different pH, and the same drug is ionized to different degrees on each side. The uncharged form crosses freely and equilibrates, but the charged form is stuck. The compartment whose pH favours ionization ends up holding more total drug, even though the free uncharged concentration is equal on both sides.

Ion trapping explains several real situations: weak bases concentrate in the acidic stomach and in acidic urine, weak acids concentrate in alkaline urine, and in poisoning the deliberate alteration of urine pH traps a drug in the tubule to speed excretion. It is the same principle that lets a base accumulate in breast milk, which is slightly more acidic than plasma.