What is membrane permeability?
Learning objectives
After reading this article you will be able to:
- Explain passive and active transport across membranes
- Compare the PAMPA and Caco-2 assays
- Describe chameleonic behaviour in macrocycles
Before an oral drug can act, it must cross the gut wall, and if its target sits inside cells it must cross the cell membrane as well. Membrane permeability measures how readily a molecule passes through these lipid barriers.
Passive and active transport
Most drugs cross membranes by passive diffusion: they dissolve into the fatty core of the membrane and come out on the other side. This favours molecules that are not too polar and not too large. Some molecules are also carried by transporter proteins; efflux transporters such as P-glycoprotein actively pump compounds back out, lowering their effective permeability.
How permeability is measured
| Assay | What it is | What it captures |
|---|---|---|
| PAMPA | Parallel artificial membrane permeability assay: a lipid-impregnated filter between two wells. | Passive diffusion only. Cheap, fast, reproducible. |
| Caco-2 | A layer of human colon carcinoma cells that behave like gut lining. | Passive diffusion plus transporters and efflux. Slower and more variable. |
| MDCK | Dog kidney cell layer, often engineered to express a transporter. | Passive permeability, or efflux by a chosen transporter. |
Results are reported as an apparent permeability coefficient (Papp) or, often, its logarithm. Because PAMPA isolates passive diffusion, it is well suited to building consistent datasets for modelling how structure affects permeability.
Chameleonic macrocycles
Macrocycles are usually too large and polar to be permeable on paper, yet some — cyclosporin A is the classic example — are absorbed well. They behave like chameleons: inside the membrane they fold so that internal hydrogen bonds bury their polar NH and OH groups, and in water they open up to remain soluble and bind their target. Designing for this behaviour, for example by N-methylating amides or placing groups to form internal hydrogen bonds, is a central skill in beyond rule of five chemistry.
Pyxis Discovery’s PAMPA measurements on macrocycles form the largest single source of consistent data in the open Membrane Permeability Database for Nonpeptidic Macrocycles, published in Scientific Data.
Last updated October 31, 2026
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