first-pass metabolism
First-pass metabolism is the tollbooth a swallowed drug must clear before it reaches the rest of the body. After absorption from the gut, blood does not flow straight to the heart; it is routed first through the liver. So the drug runs a gauntlet — gut wall, then liver — and a fraction is destroyed before it ever enters the general circulation.
Mechanistically, both the intestinal lining and the liver are rich in drug-metabolizing enzymes, especially CYP3A4 and various conjugating enzymes. As the freshly absorbed drug passes through these tissues via the hepatic portal vein, a portion is oxidized or conjugated and removed. The greater this first-pass loss, the lower the oral bioavailability, even if the drug was absorbed perfectly.
First-pass metabolism explains why some drugs need much larger oral doses than intravenous doses, and why a few are unusable by mouth altogether. It can be sidestepped by routes that bypass the portal circulation, such as intravenous, sublingual, or transdermal delivery. For prodrugs, however, first pass is desirable: the liver performs the very activation step that converts the prodrug into the active medicine.
Nitroglycerin is given under the tongue rather than swallowed precisely because its first-pass metabolism is so extensive that an oral tablet would be almost entirely destroyed before acting.
Choosing a route of administration to avoid first-pass loss.