Barriers, reservoirs and patient factors

P-glycoprotein is the best-known efflux carrier of the blood–brain barrier, and its importance comes from where it sits and what it does. It is a transporter protein embedded in the membrane of the brain capillary endothelial cells, and it uses energy to move drug from the inside of the cell back into the blood. A drug may dissolve into the endothelial membrane perfectly well and still never accumulate in the brain, because the pump removes it as fast as it arrives. The same protein is found in other barrier tissues, including the intestine, the kidney tubule and the placenta, where it has the same protective logic: it limits how much drug is absorbed, increases how much is excreted and reduces exposure of the fetus. Two practical consequences follow. First, a drug that looks ideal on paper — small, lipid-soluble, unionised — can fail centrally because it is a P-glycoprotein substrate. Second, when another drug inhibits the pump, the concentration of the substrate rises in the brain and in the blood, which can turn a safe combination into a toxic one. The pump is also saturable, so a large dose can partly overwhelm it. This is why efflux transport is now considered alongside simple lipid solubility when a drug’s access to the brain is predicted.

A reservoir changes not only how long a drug stays in the body but also how it behaves from one dose to the next. Thiopental is the clearest teaching example. After a single intravenous dose the drug enters the well-perfused brain within seconds and produces anaesthesia, but the plasma concentration then falls quickly for two reasons: the drug redistributes into muscle and, more slowly, into fat. This redistribution ends the effect of the first dose even though very little drug has been metabolised; the liver works far too slowly to explain the recovery. Fat, however, keeps filling. On a second or third dose there is less empty space to receive the drug, so more of it stays in the brain and in the plasma, and the same dose produces a deeper and longer effect. The same principle explains the prolonged sedation seen with repeated doses of a lipophilic drug in a patient with a large fat mass, and the slow release that continues after dosing stops. Reservoirs also explain organ-specific toxicity: tetracycline deposited in growing teeth, chloroquine bound in the retina and ephedrine taken up by the iris all reflect drug that has left the plasma for a tissue. When you meet a drug whose effect lasts longer than its half-life in plasma would suggest, ask where the reserve is and how full it has become.