First-pass metabolism

When a drug is administered by an enteral route (e.g. PO), it is absorbed into blood vessels that drain into the portal vein. The blood must then pass through the liver, being exposed to the drug metabolising enzymes in the liver, before it can then reach the systemic circulation, from where it can distribute to tissues and organs. If the drug is a substrate for hepatic drug metabolising enzymes (typically we are talking about CYP enzymes, but numerous other enzymes, including conjugating enzymes, could also be responsible) then some of the drug will be metabolised on this first passage through the liver. Metabolised drug never reaches the systemic circulation to have a therapeutic effect. This is called first pass metabolism.

Some drugs administered by an enteral route may undergo a degree of lymphatic drug absorption, which obviates the need for initial passage through the liver and which can increase oral bioavailability to a value greater than might be predicted based upon the hepatic extraction ratio for that drug.

When first pass metabolism is so extensive that barely any of the drug manages to escape from the liver (such as occurs with glyceryl trinitrate used to treat angina) then other routes of administration may be used. For example, glyceryl trinitrate is administered as a sublingual tablet, or in a topical adhesive patch, from which drug is absorbed through the skin.