pH-partition hypothesis

The pH-partition hypothesis is a simple, powerful rule of thumb for predicting where a drug will be absorbed: only the uncharged form of a drug slips easily across the fatty wall of a cell membrane, while the charged form is largely stuck in the water on either side. So a drug is best absorbed at the pH that keeps it mostly neutral.

Apply it to the gut and a clear picture appears. A weak acid like aspirin is mostly neutral in the acidic stomach, so the hypothesis predicts it can begin to be absorbed there. A weak base is mostly neutral in the more alkaline small intestine, so it is favoured for absorption further down. Combining a drug's pKa with the pH of each region lets you anticipate where the neutral, membrane-crossing form predominates.

The hypothesis is a useful first approximation, but reality is more generous. The small intestine absorbs the vast majority of orally given drugs regardless of their acid or base nature, because its enormous surface area, long residence time and thin, well-perfused lining outweigh the simple pH-charge argument. Active transporters and the ionised form's small but real permeability further blur the picture, so the hypothesis explains trends rather than exact outcomes.