First-pass metabolism is a drug metabolism process that occurs at specific sites in the body, primarily the liver and the intestinal wall. That results in a significant reduction of the drug's active concentration before it reaches its intended site of action or enters the systemic circulation effectively.
How It Works:
When a drug is taken orally, it is absorbed through the gastrointestinal (GI) tract.
It then enters the portal circulation, traveling directly to the liver.
In the liver, the drug undergoes extensive metabolism by enzymes (like CYP450 enzymes).
A large portion of the drug is metabolized and inactivated before reaching systemic circulation.
As a result, the bioavailability of the drug (the amount available to exert its effect) is reduced.
Drugs with High First-Pass Metabolism:
Propranolol
Nitroglycerin
Morphine
Lidocaine
Site of First-Pass Metabolism:
The liver is the primary site of first-pass metabolism. The intestinal wall is the secondary site.
Prodrugs refer to inactive compounds that are activated after metabolism (Example: enalapril → enalaprilat)
Dose Adjustment:
Dose adjustment is not so relevant nowadays because of various adverse effects. The main concept is that higher oral doses may be required to compensate for the loss during first-pass metabolism.
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