First-Pass Metabolism

Definition

First-pass metabolism (also known as first-pass effect or presystemic metabolism) is the process by which a drug’s concentration is significantly reduced before it reaches the systemic circulation. This occurs mainly in the liver and, to a lesser extent, in the gastrointestinal (GI) tract. After oral administration, the drug is absorbed from the GI tract and transported via the portal vein to the liver, where enzymes may metabolize a significant portion of it. As a result, only a fraction of the active drug reaches the systemic circulation, reducing its bioavailability.

Clinical Importance of First-Pass Metabolism

• Reduced Bioavailability: Drugs with high first-pass metabolism have lower bioavailability, requiring a higher dose for oral administration to achieve therapeutic levels.
• Dosing Adjustments: For drugs with extensive first-pass metabolism, alternative routes of administration (e.g., intravenous, sublingual) are often used to bypass the liver and ensure adequate therapeutic effects.
• Drug Interactions: Drugs metabolized by the same liver enzymes may interact, altering the effectiveness or safety of the medications.

Examples of Drugs with High First-Pass Metabolism

• Nitroglycerin: Undergoes extensive first-pass metabolism, often administered sublingually to bypass the liver.
• Propranolol: A beta-blocker with substantial first-pass metabolism, requiring careful dosing adjustments.
• Morphine: Has high first-pass metabolism when taken orally, necessitating higher doses than with other routes of administration.
• Lidocaine: Due to high first-pass metabolism, it is generally given intravenously when used as an antiarrhythmic drug.

Strategies to Improve Bioavailability of Drugs with High First-Pass Metabolism

1. Alternative Routes of Administration:

• Sublingual or Buccal: Drugs absorbed under the tongue or through the cheek mucosa (e.g., nitroglycerin) enter systemic circulation directly, bypassing the liver.
• Intravenous (IV): Directly administers the drug into the bloodstream, providing 100% bioavailability (e.g., lidocaine).
• Transdermal: Medications delivered through the skin can bypass the GI tract and liver, allowing better bioavailability (e.g., fentanyl patches).
• Rectal: Partially bypasses the liver, although some first-pass metabolism may still occur.

2. Drug Formulation Modifications:

• Prodrugs: Convert drugs into inactive or less active compounds that can bypass first-pass metabolism and are activated in the systemic circulation (e.g., enalapril is a prodrug activated into enalaprilat).
• Encapsulation or Liposomal Delivery: Protects the drug from immediate breakdown in the liver, enhancing bioavailability.

3. Enzyme Inhibitors:

Co-administering enzyme inhibitors (such as those affecting cytochrome P450 enzymes) can reduce the rate of metabolism, increasing the drug’s bioavailability.

Example: Ritonavir is used with other antiretrovirals to inhibit CYP3A4, enhancing the bioavailability of these drugs.

4. Chemical Modification of the Drug:

Modifying the drug’s structure to make it less susceptible to metabolic enzymes or enhancing its lipophilicity can improve absorption and bioavailability.