first-pass metabolism
First-pass metabolism is the breakdown a swallowed drug suffers on its very first journey through the gut wall and liver, before it ever reaches the general circulation. Imagine the drug having to pass through a toll booth and a filter on the way from the gut to the rest of the body — much of it can be removed or chemically altered before it gets through.
The route explains the effect. A drug absorbed from the intestine does not go straight into the general bloodstream; instead it is collected by the portal vein and delivered first to the liver, the body's main metabolic organ. Enzymes in the gut wall (and gut bacteria) can also act on it. By the time the drug emerges into the systemic circulation, only a fraction may remain active. This is why first-pass metabolism is a major reason oral bioavailability can be far below 100%.
The size of the first-pass effect varies enormously between drugs. Some (like glyceryl trinitrate, propranolol, or morphine) are so heavily extracted that the oral dose must be much larger than an intravenous one, or another route must be used entirely. Drugs with extensive first-pass metabolism are also more sensitive to liver disease and to enzyme-inducing or enzyme-inhibiting interactions.
Routes that bypass the portal-liver path — intravenous, sublingual, transdermal, inhaled, and partly rectal — avoid or reduce first-pass metabolism, which is often the whole reason they are chosen.
Oral glyceryl trinitrate is almost useless because the liver destroys nearly all of it on the first pass; placing it under the tongue avoids this and works in minutes.
Heavy first-pass loss is why some drugs cannot be swallowed.
First-pass metabolism is sometimes exploited deliberately: a prodrug can be designed so that the liver converts it into the active form on first pass.