Although every tissue has some ability to metabolize drugs, the liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the gastrointestinal tract, the lungs, the skin, the kidneys, and the brain.

After oral administration, many drugs are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism. This process is called the first-pass effect.

Some orally administered drugs are more extensively metabolized in the intestine than in the liver, while others undergo significant intestinal metabolism. Thus, intestinal metabolism can contribute to the overall first-pass effect, and individuals with compromised liver function may rely increasingly on such intestinal metabolism for drug elimination. Compromise of intestinal metabolism of certain drugs can also result in significant elevation of their plasma levels and clinically relevant drug-drug interactions.

First-pass effects may so greatly limit the bioavailability of orally administered drugs that alternative routes of administration must be used to achieve therapeutically effective blood levels.

Furthermore, the lower gut harbors intestinal microorganisms that are capable of many biotransformation reactions. In addition, drug may be metabolized by gastric acid, by digestive enzymes, or by enzymes in the wall of the intestine.

Although drug biotransformation in vivo can occur by spontaneous, non catalyzed chemical reactions, most transformations are catalyzed by specific cellular enzymes. At the sub cellular level, these enzymes may be located in the endoplasmic reticulum, mitochondria, cytosol, lysosomes, or even the nuclear envelope or plasma membrane.