3.8
First Pass Effect
Presystemic elimination, or the first-pass effect, is the metabolism of drugs that reduces their effective concentration at the site of action. Apart…
When a drug is given orally, it is metabolized in the intestine and the liver before reaching the systemic circulation. Such breakdown of the drug is called the first-pass effect.
Soon after ingestion, the drug is absorbed by the small intestine. The intestinal enzymes metabolize some molecules, but most are transported via the blood to the liver.
Within the liver, the drug can be metabolized or excreted through the bile. The fraction of drug the liver eliminates is known as the extraction ratio or ER. It is measured from the drug concentrations in blood entering and leaving the liver.
If a drug is completely absorbed and minimally lost by chemical degradation, the amount remaining after the first-pass effect is its bioavailability. The greater the first-pass effect, the lower the drug's bioavailability.
Drugs with high ERs are administered via sublingual and transdermal routes that provide direct access to the systemic circulation to avoid the first-pass effect.
View the full transcript and gain access to JoVE Core videos
Q1: What happens to a drug when it is taken orally?
When a drug is taken orally, it is absorbed by the small intestine and transported via blood to the liver. In the liver, the drug can be metabolized or excreted through bile before reaching systemic circulation. This presystemic breakdown reduces the drug's effective concentration at the site of action.
Q2: How does the extraction ratio relate to drug bioavailability?
The extraction ratio measures the fraction of drug the liver eliminates, calculated from drug concentrations entering and leaving the liver. The greater the extraction ratio, the more drug is removed before reaching systemic circulation. This inverse relationship means higher extraction ratios result in lower drug bioavailability and reduced therapeutic effect.
Q3: Why are sublingual and transdermal routes preferred for drugs with high extraction ratios?
Sublingual and transdermal routes provide direct access to systemic circulation, bypassing the liver and intestinal metabolism. This avoids the first-pass effect, allowing drugs with high extraction ratios to reach therapeutic concentrations without requiring higher doses. These alternative routes prevent the loss of drug potency that occurs with oral administration.
Q4: What is the relationship between first-pass effect and oral drug dosage?
Oral drug dosages must be higher than intravenous doses to achieve the same therapeutic effect because the first-pass effect reduces drug bioavailability. However, increasing oral dosage to compensate also increases plasma concentrations of toxic metabolites, potentially causing adverse effects. This creates a clinical challenge in balancing efficacy with safety.
Q5: Where can drug metabolism occur besides the liver?
Depending on the route of administration, drugs can be metabolized in the intestine, lungs, and vasculature in addition to the liver. Drugs administered by inhalation bypass hepatic first-pass metabolism but may still be excreted through exhalation by the lungs. This multi-site metabolism affects overall drug bioavailability and elimination patterns.
Q6: How do intestinal enzymes contribute to the first-pass effect?
After oral ingestion, the drug is absorbed by the small intestine where intestinal enzymes metabolize some drug molecules. Most remaining drug is then transported via blood to the liver for further metabolism or excretion. This intestinal metabolism is the first stage of presystemic elimination that reduces the amount of active drug reaching systemic circulation.
Q7: What factors besides first-pass effect reduce systemic bioavailability?
Systemic bioavailability is reduced by incomplete absorption and chemical degradation of drugs, in addition to first-pass metabolism. Incomplete absorption means not all ingested drug reaches the bloodstream, while chemical degradation breaks down drug molecules before absorption. Together, these factors determine the fraction of administered dose that reaches systemic circulation.