Learning Objective
Understand the concept of first-pass metabolism, how it affects bioavailability, and the principles of drug distribution, including protein binding, free fraction, and drug interactions.
First-Pass Effect
With oral administration, drugs are absorbed into the portal circulation and first pass through the liver before reaching systemic circulation.
- Some drugs undergo rapid hepatic metabolism, which reduces bioavailability—this is called the first-pass effect.
- Drugs that are highly susceptible to first-pass metabolism may be administered by other routes (e.g., IV, sublingual) to bypass the liver.
Clinical Correlates:
- Lidocaine: Given IV to avoid first-pass metabolism.
- Nitroglycerin: Administered sublingually to bypass extensive hepatic metabolism.
- Drugs with high plasma protein binding and a narrow therapeutic range (e.g., warfarin, phenytoin) are prone to drug interactions.
Distribution
Distribution is the process by which a drug moves from the systemic circulation to organs and tissues.
- Plasma protein binding: Most drugs bind to plasma proteins (e.g., albumin), maintaining an equilibrium between bound and free drug.
- Only the free (unbound) fraction of a drug can cross biomembranes and exert pharmacologic effects.
- Competition for binding sites can increase the free fraction of one drug, enhancing its effects.
- Example: Sulfonamides displace bilirubin in neonates.
- Under normal conditions, protein-binding capacity exceeds drug concentration, so the free fraction remains relatively constant.
