distribution
Once a drug is in the blood, it does not stay put. Distribution is the reversible spreading of the drug from the bloodstream out into the tissues and organs, and back again. Think of the blood as a delivery network and the tissues as warehouses: molecules constantly shuttle out to the warehouses and return, settling into a moving balance.
How widely a drug distributes depends on blood flow, how easily it crosses tissue membranes, how strongly it binds to proteins in the blood versus components in tissue, and its affinity for fat or water. A greasy drug may pile up in fatty tissue; a drug heavily bound to plasma proteins tends to stay in the blood. Distribution determines whether a drug reaches its target tissue — and whether it reaches places where it can cause harm, such as the brain.
Distribution is the second letter of ADME and is summarized quantitatively by the volume of distribution, an apparent volume that tells you how much the drug spreads out of the blood. A small volume suggests the drug stays mostly in the circulation; a large one means it has dispersed deep into the tissues.
Highly lipophilic anesthetics first flood the brain because of its rich blood supply, then redistribute into muscle and fat — which is why a single dose of such a drug wears off as it leaves the brain, even before it is eliminated from the body.
Redistribution can end a drug's effect without any elimination.
Only the free, unbound drug can leave the blood and act on its target; drug locked onto plasma proteins is held back, so protein binding shapes distribution.