First Pass Metabolism: A Comprehensive Overview | Study notes Pharmacokinetics

First Pass (Presystemic) Metabolism

Definition:

First pass metabolism (also called presystemic metabolism) refers to the process by which a drug

is metabolized in the liver and intestinal wall before it reaches the systemic circulation. This occurs

primarily after oral administration, but also in other routes like transdermal (skin) and pulmonary

(lungs).

Pharmacokinetics of First Pass Metabolism:

1. Oral Administration: When a drug is taken orally, it is absorbed through the

gastrointestinal (GI) tract, where it first enters the portal circulation. The drug travels via

the portal vein to the liver, which is the primary site for drug metabolism. Some of the drug

is metabolized by enzymes in the liver and the intestinal wall before reaching the systemic

circulation. This is the first pass effect.

o Intestinal Wall: Enzymes in the intestinal epithelium may also metabolize drugs

before they are absorbed into the bloodstream.

o Liver: The liver is the main organ involved in first pass metabolism. Hepatic

enzymes, including cytochrome P450 enzymes, break down the drug, which may

reduce the drug’s effectiveness and bioavailability.

2. Other Routes:

o Transdermal: Drugs administered through the skin (transdermal) may undergo

limited first pass metabolism at the skin’s surface.

o Lungs: Drugs that are inhaled or absorbed through the lungs can also be

metabolized before entering the systemic circulation.

First Pass Metabolism and Oral Bioavailability:

 Oral Bioavailability: Bioavailability refers to the fraction of an orally administered drug

that reaches the systemic circulation in an active form. High first pass metabolism reduces

the amount of the drug that reaches the bloodstream, lowering its bioavailability.

Conversely, low first pass metabolism results in a higher bioavailability.

 Impact on Drug Efficacy: Drugs with significant first pass metabolism may require higher

oral doses to achieve therapeutic effects, as a portion of the drug is metabolized before

entering circulation. The difference between the administered dose and the effective dose

can vary depending on the extent of metabolism.

Factors Affecting First Pass Metabolism:

1. Drug-Specific Factors:

o Some drugs undergo extensive first pass metabolism (e.g., lidocaine, propranolol),

while others undergo minimal metabolism in the liver (e.g., morphine, ethanol).

o The chemical structure, lipophilicity, and molecular weight of a drug influence its

susceptibility to first pass metabolism.

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First Pass (Presystemic) Metabolism Definition : First pass metabolism (also called presystemic metabolism) refers to the process by which a drug is metabolized in the liver and intestinal wall before it reaches the systemic circulation. This occurs primarily after oral administration, but also in other routes like transdermal (skin) and pulmonary (lungs). Pharmacokinetics of First Pass Metabolism:

Oral Administration : When a drug is taken orally, it is absorbed through the gastrointestinal (GI) tract, where it first enters the portal circulation. The drug travels via the portal vein to the liver, which is the primary site for drug metabolism. Some of the drug is metabolized by enzymes in the liver and the intestinal wall before reaching the systemic circulation. This is the first pass effect. o Intestinal Wall : Enzymes in the intestinal epithelium may also metabolize drugs before they are absorbed into the bloodstream. o Liver : The liver is the main organ involved in first pass metabolism. Hepatic enzymes, including cytochrome P450 enzymes, break down the drug, which may reduce the drug’s effectiveness and bioavailability.
Other Routes : o Transdermal : Drugs administered through the skin (transdermal) may undergo limited first pass metabolism at the skin’s surface. o Lungs : Drugs that are inhaled or absorbed through the lungs can also be metabolized before entering the systemic circulation. First Pass Metabolism and Oral Bioavailability:  Oral Bioavailability : Bioavailability refers to the fraction of an orally administered drug that reaches the systemic circulation in an active form. High first pass metabolism reduces the amount of the drug that reaches the bloodstream, lowering its bioavailability. Conversely, low first pass metabolism results in a higher bioavailability.  Impact on Drug Efficacy : Drugs with significant first pass metabolism may require higher oral doses to achieve therapeutic effects, as a portion of the drug is metabolized before entering circulation. The difference between the administered dose and the effective dose can vary depending on the extent of metabolism. Factors Affecting First Pass Metabolism:
Drug-Specific Factors : o Some drugs undergo extensive first pass metabolism (e.g., lidocaine, propranolol), while others undergo minimal metabolism in the liver (e.g., morphine, ethanol). o The chemical structure, lipophilicity, and molecular weight of a drug influence its susceptibility to first pass metabolism.

Enzyme Activity : o Enzyme activity in the liver and intestines plays a crucial role in determining the extent of first pass metabolism. Liver enzymes, especially the cytochrome P family, are responsible for the biotransformation of many drugs. o Differences in enzyme activity due to genetic variation, age, sex, and health status (e.g., liver disease) can significantly alter the metabolism of drugs.
Individual Variations : o Genetic Differences : Genetic polymorphisms in drug-metabolizing enzymes can lead to differences in the extent of first pass metabolism between individuals. o Age and Health Conditions : Liver function can change with age or certain health conditions (e.g., liver cirrhosis), affecting drug metabolism and bioavailability. o Food and Drug Interactions : Diet (e.g., grapefruit) or concurrent drug use (e.g., enzyme inhibitors) can alter the activity of enzymes involved in first pass metabolism. Attributes of Drugs with High First Pass Metabolism:
Higher Oral Dose vs. Sublingual or Parenteral Dose : Drugs with extensive first pass metabolism require significantly higher oral doses compared to other routes, such as sublingual or intravenous, to achieve the same therapeutic effect. This is because a significant portion of the drug is metabolized before reaching systemic circulation after oral administration.
Marked Individual Variation : The extent of first pass metabolism varies between individuals. This can lead to variations in the required oral dose to achieve therapeutic levels. For example, some individuals may metabolize a drug more efficiently, requiring a higher dose, while others may metabolize it more slowly, requiring a lower dose.
Increased Oral Bioavailability in Liver Disease : In patients with liver disease (e.g., cirrhosis), the liver’s ability to metabolize drugs may be impaired. As a result, the first pass metabolism of certain drugs is reduced, leading to increased oral bioavailability. This is important for dosing considerations in patients with compromised liver function.
Drug-Drug Interactions : Concurrent administration of drugs that inhibit or compete for the same metabolic enzymes in the liver can increase the bioavailability of a drug undergoing first pass metabolism. For instance: Chlorpromazine and Propranolol : Both drugs are metabolized by cytochrome P450 enzymes. When given together, one drug may inhibit the metabolism of the other, increasing its oral bioavailability. This interaction can lead to altered therapeutic effects and side effects.

First Pass Metabolism: A Comprehensive Overview, Study notes of Pharmacokinetics

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