First-pass Effect
Definition:
The biotransformation of a drug before it enters the systemic circulation. The most significant first-pass effect usually occurs in the liver and small intestine.
Relevance:
The losses between the site of administration and the main circulation impact how much of the unchanged drug is available systemically. In other words, the first-pass metabolism effect affects the bioavailability of drugs. The term first-pass effect is often used to refer to drugs given orally, as the intestines and liver are the major sites of drug metabolism.
Some routes of administration are less affected by first-pass metabolism. For example, a fraction of drugs given rectally go directly to the systemic circulation. Similarly, a significant fraction of drugs administered via sublingual route is transported directly to the main circulation. Although drugs administered intravenously bypass the first pass metabolism by the GI tract, they still undergo the first-pass effect in the lungs. It is important to clarify that even if a fraction or most of a given dose of a drug bypass the first-pass effect, this drug will most likely still be metabolized once it enters the main circulation.
The first-pass effect has several implications. First, drugs that are subject to extensive first-pass metabolism present low bioavailability when administered orally. To overcome this problem, one may increase the dose of the given drug or choose a different route of administration when possible. As the intravenous route often bypasses this effect, a lower dose is usually administered than that required with oral administration.
Second, the first-pass effect is one of the contributing factors to individual variability in drug response. Many of the enzymes involved in the first-pass impact are subject to genetic variability. Therefore, the degree of the first-pass metabolism varies from person to person. This variability helps explain the difference in drug response among patients; it also helps explain why some patients are more susceptible to adverse drug reactions than others.
Third, drugs subject to the first-pass effect are prone to more drug interactions. Drugs subjected to first-pass metabolism can also act as inducers and/or inhibitors of the enzymes involved in this process, thus affecting the metabolism of other drugs.
The impact of the first-pass metabolism is more significant on drugs whose metabolites are inactive or less potent. In this case, only a fraction of the active parent compound will achieve systemic circulation.
If a drug acts locally (e.g., orlistat), the first-pass effect may have little impact on the efficacy of this drug. In some cases, such as that following budesonide inhalation, this effect decreases the chances of adverse effects by reducing the systemic bioavailability of the active drug.
Examples of drugs that are subject to first-pass metabolism:
buspirone, atorvastatin, cyclosporine, felodipine, midazolam, nifedipine, propranolol
Teaching tips:
The concept of first-pass metabolism can be used to teach
- bioavailability
- differences between routes of administration
- individual variability to drug response
- food-drug interaction
- drug-drug interaction
Suggested article on this topic:
N Engl J Med 2005; 352:2211-2221. DOI: 10.1056/NEJMra032424
Linked terms: bioavailability, metabolism, routes of administration, intravenous administration, parent drug
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