3.8
Erster-Pass-Effekt
Präsystemische Elimination oder der Erster-Pass-Effekt ist der Stoffwechsel von Medikamenten, der ihre wirksame Konzentration am Wirkort reduziert. Ab…
Wenn ein Medikament oral verabreicht wird, wird es im Darm und in der Leber verstoffwechselt, bevor es in den systemischen Kreislauf gelangt. Ein solcher Abbau des Arzneimittels wird als First-Pass-Effekt bezeichnet.
Kurz nach der Einnahme wird das Medikament vom Dünndarm aufgenommen. Die Darmenzyme verstoffwechseln einige Moleküle, die meisten werden aber über das Blut in die Leber transportiert.
In der Leber kann das Medikament über die Galle verstoffwechselt oder ausgeschieden werden. Der Anteil des Arzneimittels, den die Leber eliminiert, wird als Extraktionsverhältnis oder ER bezeichnet. Es wird anhand der Arzneimittelkonzentrationen im Blut gemessen, das in die Leber ein- und austritt.
Wenn ein Medikament vollständig absorbiert wird und durch chemischen Abbau nur minimal verloren geht, bleibt nach dem First-Pass-Effekt nur noch seine Bioverfügbarkeit übrig. Je größer der First-Pass-Effekt ist, desto geringer ist die Bioverfügbarkeit des Medikaments.
Medikamente mit hohen ERs werden über sublinguale und transdermale Wege verabreicht, die einen direkten Zugang zum systemischen Kreislauf bieten, um den First-Pass-Effekt zu vermeiden.
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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.