First-pass metabolism - Definition, Reason, Site, How to bypass - imdip

First-pass metabolism also known as first-pass effect or pre-systemic metabolism is one of the most important topics before learning about the drug delivery system.

Definition of First-pass Metabolism:

First-pass metabolism is the process by which a drug is administered orally. The concentration of the drug is largely or slightly reduced by the liver and intestinal wall before reaching systemic circulation.

Related Article: Pharmacokinetics -Transportation, Absorption, Distribution, Metabolism, Excretion

Reason of First-pass Metabolism:

The liver is a key organ that metabolizes nutrients using various enzymes and helps regulate most chemical levels in the blood.

 

The liver filters all of the body's blood and breaks down poisonous substances, such as alcohol and drugs. It also produces bile, a fluid that helps digest fats and carry away waste.

Due to this metabolism, the concentration of the drug is largely or slightly reduced when taken orally.

Related Article: Bioavailability and Therapeutic Drug Monitoring

Site of First-Pass Metabolism:

The liver is the primary site of first-pass metabolism. The intestinal wall is the secondary site.

Mechanism (Step by step):

• After oral administration, the drug is absorbed into the gastrointestinal tract.
• The absorbed drug is transported to the liver via the portal vein.
• Various enzymes in the liver metabolize the drug, reducing its active concentration before it enters systemic circulation. The reduction of bioavailability of the drug occurs.

Examples of Drugs Undergoing First-pass Metabolism

Propranolol: A beta-blocker with significant first-pass metabolism.
Morphine: Extensively metabolized in the liver.
Lidocaine: Ineffective orally due to high first-pass metabolism.
Verapamil: Undergoes significant hepatic metabolism.

How to Bypass First-pass Metabolism:

Drugs with high first-pass metabolisms may require alternative routes of administration to avoid first-pass metabolisms.

• Alternative Routes of Administration
• Modified Release drug delivery system
• Uses of Prodrugs
• Dose Adjustment

Related Article:

• Targeted Drug Delivery System- Characteristics, Advantages, Disadvantages, Types, Applications
• Topical Dosage Forms- Definition, Characteristics, Advantages, Disadvantages, Classification

Alternative Routes of Administration to Avoid First-pass Metabolism:

• Sublingual (Example: Nitroglycerin)
• Intravenous (Example: Antibiotics)
• Transdermal (Example: Patches)
• Inhalation (Example: Bronchodilators)

Modified Release Drug Delivery System:

• Sustained-release formulations (SR): Gradually release the drug into the systemic circulation. (Example: Diclofenac SR tablets)
• Controlled Release (CR): This method delivers the drug at a predetermined rate over a specific time period.
• Extended Release (ER): Similar to sustained release, it releases the drug slowly over time. (Example: Metformin ER for diabetes)

Uses of Prodrugs:

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.