First pass metabolism

First-pass metabolism, also known as the first-pass effect, is the process by which a drug's concentration is significantly reduced before it reaches the systemic circulation. This phenomenon occurs primarily in the liver and the intestines, where various enzymes metabolize the drug, often leading to a decreased bioavailability. Understanding first-pass metabolism is crucial in pharmacology, as it influences the efficacy and dosage requirements of many medications.

Mechanism:

1. Oral Administration: When a drug is administered orally, it is absorbed through the gastrointestinal tract.
2. Portal Circulation: The absorbed drug enters the portal vein and is transported to the liver.
3. Metabolism in the Liver: In the liver, enzymes such as cytochrome P450 (CYP) oxidases metabolize the drug. This metabolic activity can either activate a prodrug or inactivate the drug.
4. Systemic Circulation: The remaining drug, after hepatic metabolism, enters the systemic circulation and reaches its target tissues.

Examples:

1. Propranolol:

   • Use: Beta-blocker used for treating hypertension, angina, and other heart-related conditions.
   • First-Pass Effect: Propranolol undergoes extensive first-pass metabolism in the liver, resulting in a significantly lower bioavailability (about 25%).

2. Lidocaine:

   • Use: Local anesthetic and antiarrhythmic.
   • First-Pass Effect: Lidocaine is almost completely metabolized by the liver during its first pass, which is why it is often administered intravenously for systemic use to bypass the liver.

3. Morphine:

   • Use: Opioid analgesic for severe pain.
   • First-Pass Effect: Oral morphine undergoes significant first-pass metabolism, leading to a bioavailability of about 30%.

Chemical Reactions:

1. Oxidation:

   • Example: Conversion of propranolol.
   • Reaction: Propranolol is oxidized by CYP2D6 enzymes in the liver. $\text{Propranolol}\underset{\text{CYP2D6}}{\overset{\text{Oxidation}}{\to }}\text{4-Hydroxypropranolol}$

2. Reduction:

   • Example: Metabolism of nitroglycerin.
   • Reaction: Nitroglycerin is reduced by hepatic enzymes. $\text{Nitroglycerin}\underset{\text{Reductase}}{\overset{\text{Reduction}}{\to }}\text{Glyceryl dinitrate}$

3. Hydrolysis:

   • Example: Conversion of aspirin to salicylic acid.
   • Reaction: Aspirin is hydrolyzed by esterases in the liver. $\text{Aspirin}+{\text{H}}_2\text{O}\underset{\text{Esterase}}{\overset{\text{Hydrolysis}}{\to }}\text{Salicylic acid}+\text{Acetic acid}$

4. Conjugation (Glucuronidation):

   • Example: Metabolism of morphine.
   • Reaction: Morphine undergoes glucuronidation to form morphine-6-glucuronide. $\text{Morphine}+\text{UDPGA}\underset{\text{UGT2B7}}{\overset{\text{Glucuronidation}}{\to }}\text{Morphine-6-glucuronide}+\text{UDP}$

Clinical Implications:

1. Dosing Adjustments: Due to the first-pass effect, oral doses of drugs are often higher than intravenous doses to achieve therapeutic levels.
2. Drug Formulation: Alternate routes of administration (e.g., sublingual, transdermal) are considered to bypass first-pass metabolism.
3. Inter-individual Variability: Genetic polymorphisms in metabolic enzymes can lead to variations in first-pass metabolism between individuals, influencing drug efficacy and safety.

First-pass metabolism is a critical consideration in drug development and clinical pharmacology, impacting how drugs are administered, dosed, and monitored.