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than be distributed by passive diffusion from their site of absorption, so plasma protein binding helps normalize concentrations throughout the body. ▪Drugs that are bound to plasma protein can be protected from metabolism in the liver and from excretion by the kidneys, so plasma protein binding can extend the period of time that drugs remain in the body. oBinding to plasma proteins can protect drugs from metabolism and excretion, extending the time the drugs remain in the body → but remember the general principle that drug action occurs through free, unbound drug. oProtein binding, which may include binding to proteins that are not in the plasma, also prevents the interaction of drug molecules with their site of action. oPlasma protein binding creates a reservoir of bound drug molecules that can unbind at any time to interact with drug receptors and produce responses oPlasma protein binding occurs in the plasma and encourages retention of drug in the systemic circulation. So it may appear that blood levels of a drug are high, even if the drug is not at its active site → ie: digoxin oDrugs bound to plasma proteins cannot interact with their receptor. If a drug is very strongly bound to plasma proteins, then even a small change in the fraction that is bound can have significant pharmacological effects •Transport Systems oDrug distribution is also influenced by transporters, membrane proteins that facilitate the movement of molecules across the cell membranes oTransport systems are often directional, and they can transport drugs into (influx) or out of (efflux) cells oThe transport system can transfer molecules and can create and maintain a concentration difference between two sides of the cell membrane ▪For example, when some antibiotics diffuse into cancer cells, they are transported out by the multidrug resistance protein (MRP1), which maintains a concentration gradient with the drug outside the cell